J. Org. Chem. 1991,56,513-528 1.57 (s, four CH3; '3c NMR 6 114.6 (CN), 162.5 (NC). Anal. Calcd for C13HlB05N(269.29): C, 57.98; H, 7.11; N, 5.20. Found: C, 57.87; H, 7.16; N, 5.19. Procedure B. Fractions 22-24 from the flash chromatography of 6b/8b (procedure B) gave a crystalline mass that was recrystallized from THF/petroleum ether to give a mixture of 6a and 8a: 0.3 g (2%). 2,3:4,6-Di-O-isopropylidene-B-smannopyranosylCyanide (7b) and 2,3:4,6-Di-0 -isopropylidene-@-D-mannopyranosyl Isocyanide (9b). Procedure A. The method described for 6b/8b was applied to 5a (5.0g, 19.1 mmol) to give fractions 5-11 containing 7b and 9b (a syrup): 2.8 g (54%); [aImD -36.3'; TLC R, 0.73; IR 2950,3000 (CH), 2125 (CN/NC) cm-'. Anal. Calcd for Cl3HlgO5N(269.29): C, 57.98 H, 7.11; N, 5.20. Found C, 57.46; H, 7.03; N, 4.99. Procedure B. The method described in procedure A was applied to 5b (5.0g, 19.1 mmol) and gave a syrup containing 7b and 9b: 1.9 g (37%). Purification of 7b and 9b via Preparative HPLC. The method described for the purification of 6b and 8b was applied to 7b and 9b (1 g in 2 mL of methanol). Earlier fractions containing 7b and later fractions containing 9b were collected, freed from methanol in vacuo, and extracted with CH2C12. The organic layers were dried (Na2S0 ) and concentrated in vacuo to give pure 7b and 9b. 7 b 0.2 g; [a]dD-36.40; IR (in CHCl,) 2950,3000 (CH), 2130 (CN) cm-'; 'H NMR 6 5.53 (d, H'), 4.38 (d, H2),4.27 (m, H3), 3.77 (m, H4),3.60 (m, H6), 3.71,3.97 (m, H6), 1.39, 1.45, 1.52, 1.56 (8, four CH,); 13C NMR 6 67.36 (C'), 74.22 (C2),74.89 (C3),72.13 (C4),64.83 (C5),61.42 ((2% 18.79,26.26,28.08,28.89 (four CH3), -58.7'; 100.01,110.78 (two C(CH&, 115.53 (CN). 9 b 0.5 g; [ala0~ IR (in CHCl,) 2945,3000 (CH), 2125 (NC) cm-'; 'H NMR 6 5.28 (d, H1), 4.36 (d, H2),4.26 (m, H3), 3.76 (m, H4),3.60 (m, H5),3.71, 3.94 (m, H6), 1.37, 1.43, 1.50, 1.54 (s, four CH,); 13CNMR 6 65.70 (C1),74.67 (C2),74.34 (C3),72.15 (C4),64.84 (Cs),61.40 (C6),18.81, 26.38, 28.12, 28.93 (four CH,), 100.1, 110.8 (two C(CH3)2),163.1 (NC). 2,3:5,6-Di-0-isopropylidene-a-~-mannopyranosyl Isocyanide (9a). Procedure A. Fractions 18-19 from the flash chromatography of 7b/9b (procedure A) gave a crystalline mass that was recrystallized from THF/petroleum ether to give 9a: 0.4 g (8%);mp 121-122 OC; [aImD -55.0'; T L c R10.37; IR 2960, 3000 (CH), 2140 (NC) cm-'; 'H NMR 6 5.19 (d, H'), 4.30 (m, H2-)', 3.38 (m, H6),3.83, 3.96 (m, H6), 1.40, 1.43, 1.55, 1.64 (s, four CH,); '3c NMR d 78.13 (C'), 72.82 (C2),70.51 (C3),75.52 (C4),67.50 (Cs), 62.40 ((29, 18.94, 25.56, 26.97, 28.91 (four CH,), 100.0,112.0 (two C(CH,),), 163.0 (NC). Anal. Calcd for Cl3HlgO5N(269.29): C, 57.98; H, 7.11; N, 5.20. Found: C, 57.87; H, 7.16; N, 5.19. Procedure B. Fractions 18-19 from the flash chromatography
513
of 7b/9b (procedure B) gave a crystalline mass that was recrystallized from THF/petroleum ether to give a mixture of 7a and 9a: 0.5 g (10%). This mixture was subjected to further flash chromatography with THF/methylcyclohexane (28) as the solvent. Fractions of 40-50 mL were collected. Fractions 7-8 gave pure 9a: 0.23 g (4.5%); mp 121-122 'C. 2,3:5,6-Di-04sopropylidene-a-BmannopyranosylCyanide (7a). Procedure A. Fractions 20-23 from the flash chromatography of 7b/9b (procedure A) gave a mixture of 7a and 9a that was saved to be rechromatographed: 0.2 g (4%). Fractions 24-26 of the preceding flash chromatography gave a crystalline mass that was recrystallized from THF/petroleum ether to give 7a: 0.3 g (6%); mp 148-149 OC; [ , ~ ] ~ ~ - 5 5 . 2T'L; c R 0.29; IR 2950,3000 (CH), 2140 (CN) cm-'; 'H NMR 6 4.70 (d, Hi), 4.50 (d, H2),4.13 (4, H3), 3.76 (t, H4),3.19 (m, H5),3.89 (m, He), 1.39, 1.40, 1.51, 1.60 (8, four CH,); 13C NMR 6 65.49 (Cl), 73.02 (C2),75.50 (C3), 71.75 (C4),69.94 (C5),61.54 (C6),18.80, 26.25, 28.98, 28.92 (four CH,), 111.3, 114.8 (two C(CH,),), 114.8, (CN). Anal. Calcd for Cl3HlgO5N(269.29): C, 57.98; H, 7.11; N, 5.20. Found C, 57.87; H, 7.16; N, 5.19. Procedure B. Fraction 9 of the second chromatographic purification of 9a (procedure B) gave a mixture of 7a and 9a that was saved to be rechromatographed 0.1 g (2%). Fractions 10-12 gave pure 7a: 0.17 g (3.3%); mp 148-149 OC.
Acknowledgment. This work has been supported b y an AREA grant (no. 1R15 GM38595-01 to P.H.G.) from the NIH. K.N.D. would like to thank ARCS (Achievement Rewards for College Scientists) and UOP for their financial support and Natasha Eisenbraun for her work on the purification of compounds 6b,7b,8b, and 9b. This work was taken in part from the doctoral thesis of K.N.D., University of the Pacific, 1990. We thank Dr. M. J. Minch for valuable discussions and Dr. Jim Shoolery at Varian Associates for the NMR. A preliminary report on the glycosyl fluorides (CARB#24) was presented at the 194th ACS National Meeting in New Orleans, LA (1987). A full report (CARB#39) was presented at t h e 200th ACS National Meeting in Washington, D.C. (1990). Registry No. la, 89025-46-7; lb, 78153-79-4; 2, 14131-84-1; 3, 130495-48-6;4a, 94898-41-6; 4b, 96089-62-2; 5a, 130495-46-4; 5b, 130495-47-5;6a, 13046851-8 6b, 13046852-9;7a, 130495-49-7; 7b, 130495-50-0;8a, 130468-53-0;8b, 13046854-1;9a, 130495-51-1; 9b, 130495-52-2;EhAlCN, 5804-85-3; 2-fluoro-l-methylpyridinium tosylate, 58086-67-2; 2,3,4,6-tetra-O-benzyl-~glucose, 3876881-9; D-mannOSe, 3458-28-4.
Enantioselective Syntheses of Vinblastine, Leurosidine, Vincovaline, and 20'-epi -Vincovaline Martin E. Kuehne,* Patricia A. Matson, and William G. Bornmann Department of Chemistry, University of Vermont, Burlington, Vermont 05405 Received April 20, 1990 The binary indoleindoline alkaloids vinblastine (l),leurosidine (13), 20'-epi-vincovaline (14a), and vincovaline (14b) were obtained by coupling of vindoline (3) to the tetracyclic intermediates 7a, 7b or 22a, 22b, followed by reduction and cyclization steps (60% overall yield for these reactions). The intermediates were obtained by enantioselective establishment of C20' through a first-step Sharpless oxidation (lOa,b) and followed by a subsequent diastereomeric separation (20a,bor 21a,b). Altematively, enantioselectivecontrol of the key d i n e t y p e cyclization in the reaction sequence provided the tetracyclic intermediates 54 and 60 for coupling to vindoline. Selective generation of the natural (1, 13,14a,b)or unnatural (30,34,35a,b)atropisomericforms of the alkaloids was achieved through alternative closures of ring IY. The natural products were also obtained from the higher energy atropisomers by conformational inversion on heating. For the vinblastine synthesis, the overall yield was 22%. Efforts directed toward the synthesis of vinblastine (1)' have a rich history, starting in 1967. Since there are ad0022-3263/91/1956-0513$02.50/0
equate reviews of these studies," we summarize here only their culmination for comparison with the results that are 0 1991 American Chemical Society
514 J. Ore. Chem., Vol. 56,No. 2, 1991
Kuehne et al. Scheme I1 on
presented below. Starting from the natural products catharanthine (2),a relatively rare alkaloid, and vindoline (3), the major alkaloid of Catharanthus roseus, anhydrovinblastine (4) was generated either by coupling of trifluoroacylated catharanthine N-oxide (50-60% or by coupling of catharanthine under Fe+3-promotedoxidative conditions (77%),7 followed in each case by a reduction with sodium borohydride (Scheme I). The starting material catharanthine (2) can be generated synthetically, as a racemate, by two alternative routes in 9 9 0 or ~ in 77b9 overall yield. While we have previously obtained vindoline (3) by an enantiospecific synthesis,1° natural abundance has generally provided this compound for synthetic studies. The coupling product anhydrovinblastine (4) was hydrogenated to 20’-deoxyleurosidine (5), and that (natural) product was subjected to a Polonovvky oxidation. A following oxidation of the resultant enamine 6 with thallium triacetate and a final borohydride reduction, with hydrolysis of the 20’-acetate function, then provided vinblastine (1).l1 The reported 30% overall conversion of anhydrovinblastine (4) to vinblastine (which we could confirm only in much lower yield) is surprising in view of the parallel report of Polonovsky oxidation of the amine )596
(1) Conformational representations for vinblastine (Scheme V) and other binary alkaloids shown in this paper are approximations of energy-minimized structures obtained by Timothy Spitzer, of our research group, using the Clark Still Macromodel computer program. The position numbering system is that of LeMen, J.; Taylor, W. I. Experientia 1965, 21, 508. (2) Kuehne, M. E.; Marko, I. The Alkaloids, Vol. 37; Brossi, A., Suffness, M., Eds.; Academic Press: New York, 1990. See there for the
first claimed synthesis of vinblastine: (a) Atta-ur-Rahman; Basha A,; Ghazala, M. Tetrahedron Lett. 1976,2351. (b) Atta-ur-Rahman; Wakerd, N.; Ghazala, M. 2.Naturforsch., B 1976,31, 264. (3) Cordell, G. A. Heterocyclic Compounds: The Monoterpenoid Indole Alkaloids; Saxton, J. E., Ed.; Wiley: New York, 1983; Vol. 25, p 539. (4) Lounasma, M.; Nemes, A. Tetrahedron 1982,38, 223. (5) Potier, P.; Langlois, N.; Langlois, Y.; Gueritte, F. J. Chem. SOC., Chem. Commun. 1975,670. (6) Kutney, J. P.; Ratcliffe, A. H.; Treasurywalla, A. M.; Wunderly, S. Heterocycles 1975,3,639. (7) Vucovic, J.; Goodbody, A. E.; Kutney, J. P.; Misawa, M. Tetrahedron 1988,44,325. (8)(a) Raucher, S.; Bray, B. L. J. Org. Chem. 1985,50,3237. (b)This approach has been modified, with resolution of the product. Szantay, C.; Bolcskei, H.; Gacs-Baitz, E. Tetrahedron 1990, 46, 1711. (9) Kuehne, M. E.; Bommann, W. G.; Earley, W. G.; Marko, I. J. Org. Chem. 1986,51, 2913. (10) Kuehne, M. E.; Podhorez, D. E.; Mulamba, T.; Bornmann, W. G. J. Org. Chem. 1987, 52, 347. (11) Mangeney, P.; Andriamialisoa, R. 2.;Langlois, N.; Langlois, Y.; Potier, P. J. Am. Chem. SOC.1979, 101, 2243.
5, which gave, instead of the enamine 6, only ring C’ fragmentation products.12 An improved oxygenation at C20’ was found in 1,4-reduction of the initial coupling product of catharanthine (2) and vindoline (3) by an NADH analogue, thus directly providing the enamine 6, which was then subjected to FeC1,-promoted 0~ygenation.l~ The following report describes the synthesis of an enantiomerically defined substrate 7a (Scheme IV) for coupling to vindoline (3) and the conversion of this intermediate 7a to vinblastine (1)in 61% yield. This convergent synthesis provided vinblastine in 22% overall yield. Four key stereochemical considerations had to be addressed for our synthesis of vinblastine: (1)Achievement of a C16’S,C14’R configuration was required for the product and for an anticancer activity that is based on interference with cellular microtubule formation. The desired C16’414’ parf stereochemistry could be expected as a result of coupling of a DIE-trans-D-seco-$-vincadifformine intemediate 7 with vindoline (3), as demonstrated in the synthesis of the model product 20’-deethyl-2(Y-deo~yvinblastine.’~ (2)‘Generationof one specific enantiomer (7a)of intermediate 7 by a diastereomeric separation was anticipated if precursors of intermediate 7 could be synthesized by a route that would enantioselectively fix the absolute stereochemistry at C20’.15 (3) A selective formation of the required diastereomer 7a (vs 22a) would then entail stereocontrol of the secodine-type cyclization, leading to the tetracyclic intermediate 7. (4) Finally, better control over the formation of atropisomeric binary alkaloid products was desired.14J5 All four goals were reached in the studies described below. For our synthesis of the carbomethoxyvelbanamine moiety of vinblastine (and of 20’-epi-vincovaline) we required the 4 s aldehyde 8a. This chiral aldehyde was synthesized from 2-ethyl-2-propenol (9, Scheme 11). A catalytic Sharpless epoxidation16of the allylic alcohol 9 with D-(-)-diethyl tartrate, titanium(1V) isopropoxide, and tert-butyl hydroperoxide gave 2-ethyl-2,3-epoxypropanol in 97% yield. The enantiomeric purity of this epoxide was determined through ‘H NMR spectra of its Mosher ester,17 with integration of the doublet signals at 6 4.27 and 4.19, indicating, respectively, formation of 93% of the 2R ester diastereomer derived from 10a and at most 7% of the 2s ester diastereomer derived from lob. A Grignard reaction (12) Mangeney, P.; Andriamialisoa, R. 2.;Langlois, N.; Langlois, Y.; Potier, P. J. Org. Chem. 1979, 44, 3765. (13) Kutney, J. P.; Choi, L. S. L.; Nakano, J.; Tsukamoto, H.; Mc Hugh, M.; Boulet, C. A. Heterocycles 1988,27, 1845. (14) Kuehne, M. E.; Zebovitz, T. C.; Bornmann, W. G.; Marko, I. J. Org. Chem. 1987,52,4340. (15) Kuehne, M. E.; Bornmann, W. G. J. Org. Chem. 1989,54,3407. (16) Gao, Y.; Hanson, R. M.; Klunder, J. M.; KO,S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. SOC.1987, 109,5765. (17) Mosher, D. J. Org. Chem. 1969,34, 2543.
J. Org. Chem., Vol. 56, No. 2, 1991 515
Enantioselective Syntheses of Binary Alkaloids
Scheme IV
Scheme I11
--
Ru*lonr carried out In lwo rruntlomrlc whr: a (rhown)and b OHC 88 @b nn(lanlcrrlr)
-
TW
TMSCi
76%
82%
i. A THF
I.
+ il. = 97% H
CO&H,
7a
20. 2la: C3.7,14 .pi a b . 21b: comapadlng C20 opl
.‘A
\
COZCHI
P a :C3.7. 14 rpl 7b. a b : mmrrponding CZO .pi
ii. CsH5CH2Br ill. THF,Et,N
(16b,17b)
ii. vindollne.
26a: Q‘, I,14’, 16’ rpl 26b, S b , mmspondlng 00’wi VI * 10 vinddinyi
19. (lSb, c?o rplmr)
\ Ili.KBH,
2L
i . 4 . = 80%
1h (lab, CZOrplmer)
butNF c _ _
86%
I
27a 288: C16’, 14’ opi 27b 28b mmrpmdlng CZO’ .pi
31a 31b: 00’.pi 31.:ClC, 1S.pl Slb C14’, 16,ZO’ opl
of the epoxide 10a with allylmagnesium chloride, in the presence of cuprous iodide, then gave the diol l l a in 91% yield. The hydroxy functions were masked by quantitative formation of an acetonide, using an exchange reaction with 2,2-dimethoxypropane in acetone, and the olefinic ketal 12a was then subjected to ozonolysis at -78 “C in dichloromethane, to furnish the 4s aldehyde 8a in 98% overall yield from the diol lla. Similarly, the 4R aldehyde 8b, which leads to leurosidine (13) and to vincovaline (14b) was obtained by using L-(+)-diethyl tartrate. Condensation of the aldehydes 8a (or 8b) with the indoloazepine 15a furnished, respectively, two sets of bridged azepines 16a and 17a (or 16b and 17b) as diastereomeric mixtures (Scheme III).l* Without isolation, these products were subjected to N-benzylation and rearrangement by treatment of the initial quaternary salts with triethylamine, to provide the pairs of diastereomeric tetracyclic amines Ma, 19a (or 18b, 19b) in a 1:l ratio, in 94% yield in each series. Alternatively,these tetracyclic amines could be obtained in 89% yield by condensation of the aldehydes 8a (or 8b) with the Nb-benzylated indoloazepine 15b in refluxing toluene. (See further discussion of this reaction below.) Hydrolysis of the acetonide function with aqueous hydrochloric acid (95% yield) then allowed chromatographic separation of the constituents of each diastereomeric pair of diols (1:l) 20a, 21a (or 20b, 21b) and the individual processing of each product through the following reactions: The primary hydroxyl function of each diol was converted to a tosylate derivative by reaction with p-toluenesulfonic anhydride and triethylamine, and the remaining tertiary hydroxyl group was then protected as a trimethylsilyl ether by reaction with trimethylsilyl trifluoromethanesulfonate and triethylamine. The overall yields of these reactions ranged from 70 to 72%. Coupling of the resulting tetracyclic amine acrylates 7a (or 22a, 7b, 22b) to vindoline (3) was achieved (Scheme IV) by the methodology previously described for the synthesis of 20’-deethyl-20’-deoxyvinblastine.’4Thus, chlo(18) Kuahne, M. E.; Matako, T. H.; Bohnert, J. C.; Motyka, L.; Oliver-Smith, D. J . Org. Chem. 1981, 46, 2002.
CQICnr - .
231 211: C3,7,14 op/ 23b, 24b: sonwpondlng C20 opl
@;CH,
1 (vinblartinr)
O,~H, 14b(Cll‘,lS,ZO’.pi) (vlncovallm)
rination with tert-butyl hypochlorite and reaction of the resulting chloro imines 23a (or 24a, 23b, 24b) with silver tetrafluoroborate and vindoline hydrofluoroborate, provided the tetracyclic C16’414’ parf indolenine 25a (or 26a, 25b, 26b), from which a reductive opening with potassium borohydride in acetic acid furnished the indoloazonine 27a (or 28a, 27b, 28b) in 80-8590 overall yields. The corresponding (undesired) C16’-C14’ pref diastereomers were not detected. The product structures could be assigned by correlation of the compounds’ spectra with those of the 20’-deethyl20’-deoxy compounds that were characterized earlier,14 with particular attention to the characteristic chemical shift values of the vindolinyl ethyl CH3 triplets in the ‘H NMR spectra. Notably, this signal is found in the vinblastine-type C16’-C14’ stereochemical arrangement at 6 0.8, downfield from the signals in the alternative stereochemical arrangements. Attempts to obtain cyclization of the vinblastine precursor tosylate 27a by heating it in toluene, according to the procedure that had given such cyclization in the 20’deoxyI5and in the 20’-deethyl-2O‘-deoxy series,I4gave only recovered tosylate 27a after 2 weeks in toluene at reflux. However, in refluxing methanol, the quaternary salt 29a was formed in 48 h. Hydrogenolysis of its benzyl substituent and cleavage of the silyl ether with fluoride ion then provided vinblastine (1) in its natural atropisomeric form in 78% overall yield from the tosylate 27a. Indirectly, the silyloxy tosylate 27a also provided access to a selective synthesis of the higher energy atropisomer 30 of vinblastine (Scheme V). Cleavage of the trimethylsilyl ether function of 27a with tetrabutylammonium fluoride, in tetrahydrofuran, cleanly produced the epoxide 31a (Scheme IV). An anti-periplanar opening
Kuehne et al.
516 J. Org. Chem., Val. 56,No. 2, 1991 Scheme VI
Scheme V
3%:b CW, lb', 51
1
I'r p l 3&: CW, lb', I'epl
It
Pd'H2
JI
--
*
$'
1(14b: (VLWClO',lb',20'*p0
(vlncovrllnm)
13 (Iwmnldlna) 1M: CW, lb', I'epl
30 (34: C10',14',20'ep0
of the epoxide ring on intramolecular alkylation of Nb'in this compound (31a) requires a transition state with a piperidine chair (Scheme V), which is conformationally isomeric with that found in natural vinblastine. Consequently, formation of only the higher energy atropisomer 30 of vinblastine could be expected after debenzylation of the initially formed quaternary salt 32a. Not as clear, however, was the feasibility of the initial quaternization reaction, considering that the reverse process, namely, formation of tertiary amine epoxides, is usually observed on treatment of 8-hydroxy quaternary salts with base.I9 While the epoxide 31a indeed remained unchanged after several days in refluxing xylene, and was destroyed in refluxing dimethylacetamide, it was converted to the quaternary salt 32a in refluxing methanol. Debenzylation by hydrogenolysis then provided the higher energy atropisomer 30 of vinblastine in 89% overall yield from the epoxide 31a. This product, which shows remarkable chromatographic retention due to its relatively unshielded Nwelectron pair and ita equatorial C20' hydroxyl function, was converted to the natural, chromatographically less polar atropisomer of vinblastine (1) on heating in toluene (95% yield). For a synthesis of vincovaline (14b), the C14',16',20' epimeric trimethylsilyloxy tosylate 28b was subjected to the same cyclization, debenzylation, and hydrolysis conditions as the isomer 27a, to provide the product in its natural atropisomeric form. Passage through an epoxide intermediate (33b) again allowed initial isolation of the compound as a higher energy atropisomer (34) and its subsequent conversion to the natural conformation 14b by heating in toluene. Cyclization of the C20'R epoxide 31b (Scheme VI), obtained from the corresponding trimethylsilyloxy tosylate 27b with tetrabutylammonium fluoride, might be expected to lead, after debenzylation, directly to the lower energy (natural) atropisomeric form of leurosidine (13) on the basis of the same stereoelectronic arguments that predict the cyclization of the C20'S epimer 31a to result in the higher energy (unnatural) atropisomer 30 of vinblastine. However, when the epoxide 31b was heated for 48 h in methanol and 1.5 equiv of acetic acid and the quaternary salt product was debenzylated, only the higher energy atropisomer 35b of leurosidine was formed. This result can be understood by consideration of the 1,3,5-triaxial alkyl substitution that would arise on cyclization in the pre-piperidine chair conformation 36, which would lead (19) Cope, A. O w . React. 1960,11, 317 (see pages 352,390, 391).
to the lower energy atropisomer of leurosidine (13). To avoid this steric compression,the alternative pre-piperidine boat conformation 31b, which leads to the higher energy atropisomer 35b of leurosidine, thus becomes preferable. Addition of acetic acid to this cyclization reaction was found to minimize deacetylation of the vindoline moiety that occurred by the otherwise generated alkoxide ion. A higher energy atropisomer was also obtained in the synthesis of 20'-epi-vincovaline. Thus desilylation of the TMS tosylate 28a provided the epoxide 33a (97% yield), which on cyclization in methanol and acetic acid, followed by debenzylation,then gave the higher energy atropisomer 35a of 20'-epi-vincovaline. Its conformational inversion in refluxing toluene (97%) provided the lower energy atropisomer 14a in 93% yield from the epoxide 33a. Distinction of the binary indole-indolines having the "unnatural" higher energy atropisomeric form (30, 34, 35a,b) was consistent with an earlier observation on the corresponding 20'-deethyL20'-deoxy c~mpound.'~ Thus, these compounds, with an equatorial Nwelectron pair, were very much more strongly adsorbed on TLC, and their Wenkert-Bohlmann IR peaks (now due only to the vindoline moiety) were diminished relative to the lower energy atropisomers 1, 13, and 14a,b. The "unnatural" atropisomers 30,34, and 35a,b showed broadening of most NMR signals due to the conformational mobility of the ninemembered ring, and their circular dichroism ellipticities at 304-310 nm had a reverse sign relative to the natural conformers 1, 13, and 14a,b.14 The final problem to be addressed was one of overcoming the intrinsic achirality of the secodine-type cyclization step. While we had observed a small diastereoselectivity in the rearrangement of bridged indoloazepines to Dseco-$-vincadifforminederivatives in the 20'-deoxy series (compare Scheme 111),15this was not found in the present work, where the 20' H is replaced by a 20' oxygen substituent. However, the generation of tetracyclic intermediates of type 18 or 19 by reactions of N-alkylated indoloazepines (i.e., 15b) with aldehydes suggested an opportunity for achieving the desired enantioselectivity.m This reaction was based on our earlier observation that the Nb-H indoloazepine ester 15a rearranged to methylene lactam 37 on heating,2I presumably through fragmentation to primary amine acrylate intermediate 38 (R' = H), and its cyclization (Scheme VII). Trapping of the corre(20) Legseir, B.;Massiot, G.; Gulhem, J.; Vercauteren, J. Tetrahedron Lett. 1987,28, 3573. (21) Unpublished resulta obtained in 1980 with Linda Motyka and Stephen Kuehne.
J, Org. Chem., Vol. 56, No. 2, 1991 517
Enantioselective Syntheses of Binary Alkaloids
Scheme IX
Scheme VI1
I
-Ho
a7
/
J
4
Scheme VI11
diol %
-I
nutions in analogy 10 schema 4 I e u d d l n e atmpieomer 35
*'
C_
epoxide 59
trimsthylailyloxytosylate 58
kuroaldh (13)
Scheme X
sponding N-benzylated acrylate intermediate 38 (R' = benzyl) with a variety of aldehydes had then led (through transient secodine analogues 39) to the formation of tetracyclic amine models 40 for the required intermediates 18 and 19.21 In order to maximize steric and possible *-stacking effects in this key intramolecular (formal) Diels-Alder reaction,= we chose chiral a-phenethyl and a-naphthylethyl Nb substituents (in place of Nb-benzyl) for our secodinetype cyclization.'8T21 The required indoloazepine intermediates 41 and 42 could be readily synthesized from corresponding N-substituted 4-piperidones (Scheme VIII). The latter compounds were obtained by replacement of dimethylamine from N-methyl-4-piperidone methiodide (45) by commercially available (S)-(-)-a-methylbenzylamine (46)or by (8)-(-)-l-(l-naphthy1)ethylamine (47).23 A Fischer indole synthesis with subsequent chlorination of the resulting y-carbolines 48 and 49 and reaction of the chloroindolenine products 50 and 51 with thallium dimethyl malonate, followed by a decarbomethoxylation of the diesters 52 and 53,24provided the indoloazepines 41 (31%, overall) and 42 (27%, overall). For a synthesis of leurosidine (13),the a-phenethylamine derivative 41 was heated in toluene with the 4R aldehyde 8b (Scheme IX),to produce a 3:l ratio of the 3&,4S di(22) Oppolzer, W. Angew. Chem., Int. Ed. Engl. 1984,23, 876. (23) An analogous reaction of the piperidone methiodide 45 with tryptamine had been developed in our laboratoriee by R. Muth. (24) Kuehne, M. E.; Kirkemo, C. L.; Matako, T. H.; Bohnert, J. C. J. Org. Chem. 1980,46,3259.
i atropieomer 30
-
Vinblastine(1)
astereomer 54 to the 3aS,4R diastereomer 55, as seen from integration of the Na 'H NMR signals at 6 8.98 and 8.87. Hydrolysis of the acetonide function of these produds then allowed chromatographic separation of the corresponding diols 56 and 57 (3:1, 47% overall yield from the azepine 41). Derivatization of the major isomer to the (trimethylsily1)oxytosylate 58 (73%), a coupling to vindoline, conversion to the epoxide 59 (73% overall), and ita cyclization and hydrogenolysis, according to the procedures used with the Nb'-benzyl compounds 7b-31b, again provided the higher energy atropisomer 35b of leurosidine, which on heating gave leurosidine (13). The (naphthylethy1)-substitutedindoloazepine 42 was used for a synthesis of vinblastine. Its condensation with the 4 s aldehyde 8a provided the tetracyclic amines 60 and 61 in a 4 1 ratio (SchemeX). Chromatographic separation
518 J. Org. Chem., Vol. 56, No.2, 1991
of the diols 62 and 63,obtained by hydrolysis of the acetonides 60 a n d 61, gave the more polar 3aR,4S isomer 62 in 37% overall yield. Ita conversion t o t h e (trimethylsily1)oxy tosylate 64 (38% yield), a coupling reaction with vindoline and formation of t h e epoxide 65 (72% overall), was followed by a cyclization that required 40 h of heating in methanol. Hydrogenolysis of the quaternary product's naphthylethyl substituent led exclusively t o t h e higher energy atropisomer 30 of vinblastine. On heating in toluene, this product was also converted to vinblastine (1) in its natural conformation (80% overall yield in the last steps starting with the cyclization of the epoxide 65).
Experimental Section General Methods. All reactions were run under a nitrogen atmosphere unlessotherwise stated. Melting points were obtained on a Kofler micro hotstage with thermometers calibrated against a National Bureau of Standards certified set. NMR spectra were obtained with Bruker 250-MHz or 270-MHz instruments and chemical shifts are expressed as parts per million (6) downfield from tetramethylsilane. Mass spectra were obtained with a Finnigan 4610 quadrupole instrument at 70 eV, calibrated with perfluorotributylamine and hexafluorotriphenyl-s-triazinefor higher molecular weight compounds. Chemical ionization spectra employed methane as the reagent gas. IR spectra were obtained with either a Nicolet 6000 FT or a Perkin-Elmer 1430 grating instrument. Perkin-Elmer 402 and Lambda instruments were used for recording UV spectra. TLC data were obtained with E. Merck 60 PF 254 precoated silica gel on aluminum sheets. Indole derivatives were characterized with a 10% solution of ceric ammonium sulfate (CAS) in phosphoric acid as a spray reagent and other compounds were visualized by either UV, iodine vapor, or treatment with an acid and heating. Flash chromatography employed Baker 7024-R 40-pm diameter silica gel. Microanalyses were provided by Robertson Laboratories, Florham Park, NJ. Circular dichroism (CD) spectra were obtained in dry methanol, using an Autodichrograph V (ISA Jobin-Yvon) instrument and Darrel R. McCaslin CD soft, V.3.1. (2R)-2-Ethyl-2,3-epoxypropanol (loa). Under argon, dichloromethane (160 mL) and powdered activated 4.0-A molecular sieves (3.0 g, Aldrich) were stirred in a three-neck flask equipped with a thermometer, a dropping funnel, and a septum and cooled to 0 "C. D-(-)-Diethyl tartrate (1.26 g, 6.11 mmol) and titanium(1V) isopropoxide (1.38 g, 4.85 mmol) were added sequentially. After 1 h the reaction was brought to -20 "C (dry ice, carbon tetrachloride) and tert-butyl hydroperoxide (85 mL, 25 mmol, 3.0 M in 2,2,4-trimethylpentane) was added, and the mixture stirred for 10 min and 2-ethylallyl alcohol (8.78 g, 102 mmol in 3 mL of dichloromethane) was added dropwise with vigorous stirring over 30 min. The reaction mixture was stirred for 4 h at -20 "C, stored at -15 "C for 12 h and then quenched with water (28 mL), allowed to warm to room temperature, and stirred another 30 min. The tartrate was hydrolyzed by addition of 7.0 mL of a 30% aqueous solution of sodium hydroxide saturated with sodium chloride and stirring for 2 h. The mixture was filtered through Celite, the organic layer was separated, and the aqueous phase was extracted with dichloromethane (100 mL). The combined organic layers were dried over magnesium sulfate and filtered. Concentration, low pressure chromatography on a 4 X 25 cm column of silica gel, eluting with 2:l ether/hexane, and distillation gave the title compound as a clear colorless oil (10.2 g, 97%, bp 77 "C, 18 mm): TLC R, 0.24 (silica gel, 1:l ether-hexane, CAS char tan); IR (neat) v,, 3436,3052,2974,2940,2882,1464, 1239,1198,1146,1080, 1042,1006,912,889,814,686 cm-'; 270-MHz 'H NMR (CDC13) 6 0.95 (t, J = 7.5 Hz, 3 H), 1.51-1.65 (m, 1 H), 1.74-1.88 (m, 1 H), 2.56-2.61 (m, 1H, OH,varies), 2.68 (d, J = 4.7 Hz, 1 H), 2.86 (d, J = 4.7 Hz, 1 H), 3.62 (dd, J = 12.3, 7.90 Hz, 1H), 3.77 (dd, J 12.3,4.9 Hz, 1H); 67.9-MH~"C NMR (CDC1.J 6 8.43, 24.49, 49.37,60.40,62.84; mass spectrum m/z (re1 intensity) 103 (M + l),91 (6),89 (41, 87 (8),85(21, 79 (l),77 (2), 73 (7), 72 (42), 71 (17), 69 (3), 59 (8),58 (3), 57 (1001, 55 (lo), 54 (5), 53 (5); high resolution mass spectrum (PCI/NH3, mass resolution 4OOO), calcd for M + NH4+ 120.10244, found 120.10258. Note: Chromatog-
Kuehne e t al. raphy prior to distillation was necessary for high yields. A 270-MHz 'H NMR analysis of the Mosher ester17(derived from (R)-(+) a-methoxy-a-(trifluoromethy1)phenylaceticacid) in CDCl, showed two doublets at 6 4.27 and 4.20 in a corresponding ratio of at least 93:7, indicating (conservatively) an 86% ee on formation of the 2R alcohol loa. (2S)-2-Ethyl-2,3-epoxypropanol (lob). By the same procedure, and employing L-(+)-diethyltartrate, a 97% yield of the enantiomeric title compound was obtained: TLC R, 0.24 (silica gel, 1:l ether-hexane, CAS char tan);IR (neat) u,, 3430,3062,
2980,2945,2888,1465,1400,1366,1328,1274,1240,1198,1150, 1082,1040,1008,987,912,890,814,735,702,687 cm-'; 270-MHz 'H NMR (CDC13)6 0.95 (t, J = 7.5 Hz, 3 H), 1.52-1.66 (m, 1H), 1.74-1.88 (m, 1H), 2.68 (d, J = 4.7 Hz, 1H), 2.86 (d, J = 4.7 Hz, 1 H), 2.95-3.00 (m, 1 H, OH, varies) 3.61 (m, J = 12.3, 7.6 Hz, 1H), 3.77 (m, J = 12.4,5.1 Hz, 1H); 67.9-MHz 'V NMR (CDCl3) 6 8.37,24.32,49.31,60.46,62.71;mass spectrum,m/z (re1intensity) 103 (M + 1,23), 91 (12), 85 (30), 73 ( E ) , 72 (39), 71 (15), 67 (14), 59 (13), 57 (loo), 55 (28); high resolution mass spectrum (PCI/ NH3, mass resolution 3000), calcd for M + Mi4+120.10244, found 120.10182. A 270-MHz 'H NMR (CDC1,) analysis of the Mosher ester17 acetic acid), (from (R)-(+)-a-methoxy-a-(trifluoromethy1)phenyl by integration of doublets at 6 4.27 and 4.20, showed a corresponding ratio of diastereomers of at most 7:93, indicating an ee of >86% on formation of the 2 s alcohol lob. (25)-2-Ethyl-2-hydroxyhex-5-enol (1 la). Under argon, a mixture of (2R)-2-ethyl-2,3-epoxypropanol (loa,5.34 g, 51.8 mmol) and copper iodide (985 mg, 5.2 mmol) was stirred in tetrahydrofuran (100 d)and brought to -30 "C (dry ice, acetonitrile). Allylmagnesium chloride (65 mL, 2 M in THF, 2.5 equiv) was added via a dropping funnel at such a rate as to maintain the temperature between -25 and -30 "C for 1 h. The reaction mixture was stirred for 6 h, stored at -15 "C for 12 h, then brought to 0 "C, and poured into 300 mL of ice-cold 1N HCL. The THF layer was separated and the aqueous phase was extracted with ether (5 X 100 mL). The organic layers were combined, dried over magnesium sulfate, concentrated, and chromatographed on a 3 X 25 cm column of silica gel, eluting with 1:l hexane/ether. Concentrationof the eluate (fractions360-660 mL) and distillation gave the title compound as a clear colorless oil (6.85 g, 91%, bp 74-75 OC/O.2 mm): TLC R 0.26 (silica gel, 5% methanol in dichloromethane, CAS char 6rown); IR (neat) u,, 3416, 3078, 2974,2942,2883,1640,1462,1416,1336,1134,1056,994,909,740,
650 cm-'; 270-MHz 'H NMR (CDC13) 6 0.89 (t,J = 7.5 Hz,3 H), 1.50-1.60 (m, 4 H), 2.05-2.17 (m, 2 H), 2.21 ( 8 , 2 H), 3.48 (9, 2 H), 4.96-5.09 (m, 2 H), 5.80-5.86 (m, 1H); 13C NMR (CDC13) 6 7.90, 27.68, 28.47, 34.52,67.54, 74.83, 114.41, 138.72; mass spectrum, m/z (re1intensity) 145 (M 1,0.4), 127 (5), 115 (6), 114 (2), 113 (28),110 (3), 109 (36),97 (3),89 (18), 88 (2),86 (7),85 (3),84 (121, 79 (3), 72 (4),71 (8),69 (5),67 (11),57 (100),55(10); high resolution mass spectrum (PCI/NH3, mass resolution 4000), M + NH4 calcd 162.14932, found 162.14958. (2R)-2-Ethyl-2-hydroxyhex-5-enol (llb). By the same procedure, starting from (2S)-2-ethyl-2,3-epoxypropanol (lob), 71 91% yield (bp 85 "C/5-6 mm) of the title compound was obtained IR (neat) u- 3400,3085,2975,2948,2890,1642,1418, 1337, 1136, 1057, 992,911, cm-l; 270-MHz 'H NMR (CDC13) 6 0.89 (t,J = 7.5 Hz, 3 H), 1.48-1.59 (m, 4 H), 2.03-2.12 (m, 2 H), 2.46 (br s, 1H), 2.82 (br s, 1H) 3.44 (8, 2 H), 4.93-5.08 (m, 2 H), 5.75-5.91 (m, 1 H); mass spectrum, m / z (re1 intensity) 145 (M + 1,4), 127 (24), 115 (8), 114 (4), 113 (381, 110 (111, 109 (loo), 97 (5), 95 (6),89 (23), 71 (13), 69 (8),67 (21), 57 (89); high resolution mass spectrum (PCI/NH3,mass resolution 30001, M + NH4 calcd 162.14932, found 162.14810. (2S)-2-Ethyl-2-hydroxyhex-5-enol Acetonide (12a). A solution of (2S)-2-ethyl-2-hydroxyhex-5-enol (lla, 1.7 g, 11.8 m o l ) in acetone (25 mL) was stirred with 2,2-dimethoxypropane(2 mL) and a catalytic amount of p-toluenesulfonic acid. After 12 h, the reaction was complete as indicated by TLC. The acetone was removed under reduced prossure at room temperature, and the residue was basified with aqueous saturated sodium bicarbonate and extracted with ether (3 x 50 d)The . combined ether layers were dried over sodium sulfate. Concentration and distillation (75-80 "C, 10 mm) gave 2.1 g of the title product (99%): TLC R, 0.72 (silica gel, 4:l hexane-ether); IR (neat) u,- 3080, 2995,
+
J. Org. Chem., Vol. 56,No.2, 1991 519
Enantioselective Syntheses of Binary Alkaloids
2950,2880,1640,1457,1255,1214,1119,1065,995,912,868,810, hexanelether, gave 3.78 mg of the title products (97% yield): "LC R, 0.32 (silica gel, 1:l ether-hexane, CAS blue); UV (ethanol) A327,297,202 nm; IR (KBr),,v 3382,2982,2938,2860,2787,1678, 1610,1478,1466,1438,1378,1368,1345,1294,1280,1249,1206, 1150,1124,1101,1054,745,700cm-'; 270-MHz 'H NMR (CDClJ 6 0.73-0.88 (m, 3 H), 0.89-0.98 (m, 1 H), 1.02 (s, 1H), 1.16-1.40 + (m, 7 H), 1.52-1.79 (m, 3 H), 1.95-2.01 (m, 2 H), 2.51-2.96 (m, 5 H), 3.46 (t, J = 7.8 Hz, 1H), 3.65-3.74 (m, 2 H),3.76-3.78 (28, 3 H), 4.18-4.28 (m, 1 H), 6.78-7.45 (m, 9 H), 8.94-8.96 (br s, 1 H); mass spectrum, m/z (re1intensity) 503 (9), 502 (M+, 31), 487 (5),374 (21), 373 (89), 369 (ll),341 (3), 332 (6), 289 (5),288 (33), 261 (3), 241 (7), 238 (6), 229 (4), 228 (29), 214 (ll),200 (5), 194 (8), 180 (9), 168 (16), 167 (ll),154 (9). 129 (ll), 120 (6), 91 (loo), 59 (13). Anal. Calcd for C31H38N201:C, 74.08; H, 7.62; N, 5.57. Found C, 73.81; H, 7.11; N, 5.31. (3aR,4R)- and (3aS,4S)-Methyl 3-Benzy1-2,3,3a,4,5,7hexahydro-4-[ ( 2 s )-2-ethyl-2,3-dihydroxypropyl]-lHpyrrolo[2,3-d]carbazole-6-carboxylate (2Oa, 21a). The mixture of the title compounds' acetonide (Ma, 19a, 500 mg, 1.0 mmol) was heated for 15 min at reflux in 25 mL of methanol, containing 10 mL of 10% aqueous hydrochloric acid. The methanol was removed under reduced pressure, and the solution was basified with ammonium hydroxide and then extracted with ether (3 X 50 mL). Concentration gave 440 mg (95%) of the title diols. + Separation of the diastereomers (400 mg)was partially effected by flash chromatography on a 5 X 12 cm silica gel column, eluting with 0.2% triethylamine in ether, to give 175 mg of the less polar 3aS,4S title isomer 21a: TLC Rf 0.32 (silica gel, ether, CAS blue). This was followed by 110 mg of the more polar 3&,M title isomer 20a, TLC Rf 025 (silica gel, ether, CAS blue-fade to purple), and 110 mg of a mixture of the two isomers. For the 3aR,4R isomer 20a: UV (ethanol) A- 329,297,225,202nm; IR (KBr),,v 3440,
735 cm-'; 270-MHz 'H NMR (CDClJ 6 0.90 (t, J = 7.5 Hz, 3 H), 1.40 (s,6 H), 1.56-1.71 (m, 4 HI, 1.98-2.18 (m, 2 H), 3.76 (8,2 H), 4.94-5.07 (m, 2 H), 5.77-5.91 (m, 1H); 13C NMR (CDC13) 6 8.35, 27.20,28.45,30.00,36.20,72.60,83.60,109.04,114.31,138.70;mass spectrum, m / z (re1 intensity) 185 (M 1, 3), 170 (€9,169, (80), 165 (4), 163 (E),156 (3), 155 (36), 149 (3), 130 (8),129 (86),127 (13), 113 (3), 111 (6), 110 (6), 109 (74), 103 (5), 97 (12), 95 (3), 85 (7), 83 (5),81 (9),79 (lo), 73 (7),72 (100),71(26),69 (23),68 (151, 67 (56),61 (4), 59 (57),57 (20),56 (3),55 (36),53 (6);high rwlution mass spectrum (PCI/NH3, mass resolution 5000),M + H calcd 185.154145, found 185.15472. (2R)-2-Ethyl-2-hydryhex-5-enol Acetonide (12b). By the same procedure, starting from (2R)-2-ethyl-2-hydroxyhex-5-enol (llb), a 99% yield of the title compound was obtained IR (neat) vmu 3081, 2992, 2950, 2880, 1644, 1457, 1382, 1371, 1256, 1214, 1161,1118,1065,995,912,868,810,735cm-'; 270-MHz 'H NMR (CDCI,) 6 0.90 (t, J = 7.5 Hz, 3 H), 1.39 (8, 6 H), 1.54-1.70 (m, 4 H), 1.99-2.20 (m, 2 H), 3.75 (s, 2 H), 4.94-5.08 (m, 2 H), 5.76-5.91 (m, 1 H); mass spectrum, m / z (re1 intensity) 185 (M + 1,8), 169 (loo), 155 (42), 129 (82), 127 (22), 11 (lo), 109 (97), 106 (13), 97 (16), 81 (15), 79 (21), 72 (79), 70 (14), 69 (28),67 (511, 59 (44),57 (32), 55 (40), 53 (11);high resolution mass spectrum (PCI/NH3, mass resolution 3000), M H calcd 185.154145, found 185.15419. (4S)-4-Ethyl-4,5-dihydroxypentanal Acetonide (sa). A solution of (2S)-2-ethyl-2-hydroxyhex-5-enol acetonide (12a, 1.02 g, 5.54 mmol) in dichloromethane (25 mL) was brought to -78 OC (dry ice, acetone), and ozone was bubbled through until the reaction mixture turned a pale blue (approximately 15 min). The reaction mixture was then flushed with nitrogen for 1 h, triwas added, and the mixture phenylphosphine (850 mg, 3.26 "01) was allowed to slowly warm to room temperature. After 24 h the solvent was removed under reduced pressure and the residue was taken up in hexane, filtered, and again concentrated. Chromatography on 50 g of silica gel, eluting with 10% ether in hexane, gave 1.01 g (98%) of the title aldehyde: TLC Rf 0.39 (silica gel, 3 2 hexaneether); IR (neat),,v 2995,2948,2889,2828,2725,1731, 1460, 1382, 1371, 1255, 1212, 1185, 1117, 1063, 987, 876 cm-'; 270-MHz 'H NMR (CDCl3) 6 0.90 (t, J = 7.6 Hz, 3 H), 1.39 (8, 6 H), 1.59-1.65 (m, 2 H), 1.90 (t, J = 7.4 Hz, 2 H), 2.53-2.61 (m, 2 H), 3.78 (9, J = 20.8, 8.7 Hz, 2 H), 9.82 (8, 1 H); 67.9-MH~ NMR (CDCl3) 6 8.32,26.77, 27.00,28.71,30.11,38.73,72.22,82.73, 109.26, 201.46; mass spectrum, m/z (re1 intensity) 187 (M 1, lo), 172 (6), 171 (62), 157 (19), 130 (4), 129 (601,127 (18),115 (6), 112 (4), 111 (54),99 (37),93 (20), 85 (12), 84 (3),83 (16),81 ( l l ) , 73 (8), 72 (loo), 71 (30), 69 (13), 67 (9), 59 (45), 57 (22), 56 (3), 55 (39), 53 (5); high resolution mass spectrum (PCI/NH3 mass resolution SOOO),M H calcd 187.13341, found 187.13259. (4R)-4-Ethyl-4,5-dihydroxypentanal Acetonide (8b). By the same procedure, starting with (2R)-2-ethyl-2-hydroxyhex-5enol acetonide (12b), a 98% yield of the title compound was obtained IR (neat),,v 2988,2940,2882,2820,2720,1729,1458, 1413, 1380, 1369,1252,1210,1182,1160,1150,1115,1060,987, 920,875,795, cm-'; 270-MHz 'H NMR (CDCl,) 8 0.90 (t, J = 7.6 Hz, 3 H), 1.38 (8,6 H), 1.54-1.69 (m, 2 H), 1.90 (t, J = 7.4 Hz, 2 H), 2.41-2.61 (m, 2 H), 3.78 (q, J = 20.8,8.7 Hz, 2 H), 9.82 (s, 1H); mass spectrum, m/z (re1intensity) 187 (M + 1,8),171 (78), 157 (24), 129 (89), 111 (75), 99 (42), 93 (24), 83 (24), 72 (loo),71 (25), 69 (16), 59 (40), 57 (27), 55 (42); high resolution mass spectrum (PCI/NH,), M + H d c d 187.1334097,found 187.13390. (3aR,4R)- and (3aS,4S)-Methyl 3-Benzyl-2,3,3a,4,5,7hexahydro-4-[ (2S)-2-ethyl-2,3-(isopropylidenedioxy)propyl]-lH-pyrrolo[2$-d]carbazole-6-carboxylate(1% 19a). A solution of 2.00 g (8.19 mmol) of methyl 1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5-carboxylate (15a) and 1.68 g (9.01 mmol, 1.1equiv) of (4.'3)-4-ethy1-4,5-dihydroxypentanalacetonide (8a) in 50 mL of tetrahydrofuran was heated at reflux under nitrogen until TLC showed no remaining starting material (approximately 2 h). After addition of anhydrous sodium sulfate and filtration, the solvent was removed under reduced pressure and the residue was taken up in 35 mL of dry tetrahydrofuran and 1.54 g (9.01 mmol) of benzyl bromide. The reaction mixture was heated at reflux for 12 h. Filtration gave 4.56 g (97%) of quaternary salta, which were heated for 2 h in 50 mL of methanol and 5.55 mL (39.8 mmol) of triethylamine. Flash chromatography of the residue on a 23 X 3.5 cm silica column, eluting with 3:2
+
+
3390,2970,2934,2880,2855,2790,1674,1610,1480,1466,1438,
1382,1344,1304,1296,1280,1250,1202,1128,1102,1076,1050, 746,700 cm-l; 270-MHz 'H NMR (CDC13)6 0.78 (t, J = 7.4 Hz, 3 H), 0.884.91 (m, 1H), 1.01-1.22 (m, 2 H), 1.46-1.51 (m, 2 H), 1.65 (dd, J = 11.7, 4.5 Hz, 1 H), 1.88 (br s, 1 H), 1.98-2.12 (m, 3 H), 2.49-2.68 (m, 3 H), 2.87-2.5 (m, 1H), 3.12 (s, 1H), 3.12 (8, 1 H), 3.3 (8, 1 H), 3.72-3.77 (m, 1 H), 3.78 (8, 3 H), 4.21 (d, J = 13.5 Hz, 1H), 6.79-6.87 (m, 2 H), 7.00 (d, J = 7.2 Hz, 1H), 7.13 (t, J = 7.7 Hz, 1 H), 7.25-7.43 (m, 5 H), 8.87 (br s, 1H); 67.9-MHz 13CNMR (CDC13) 6 7.95, 24.65,28.86, 34.23,36.56,42.79, 50.87, 55.32,58.40,65.71,67.84,74.49,75.25, 76.36,91.34, 109.21,120.64, 122.18,126.99,127.77,128.13,128.28,128.81,137.98,139.56,143.07, 165.62, 169.08; mass spectrum, m / z (re1 intensity) 463 (M 1, 6), 462 (M', 24), 431 (8), 374 (41), 332 (6), 329 (22), 249 (7), 248 (46), 238 (7), 228 (14), 215 (7), 194 (7), 180 (8), 168 (13), 167 (lo), 154 (8), 141 (5), 120 (6), 92 (8), 91 (loo), 68 (5), 57 (6); high
+
resolutioq mass spectrum (EI, mass resolution 6000), calcd for CUHMNzO4462.25184, found 462.25186. For the 3aS,4S isomer 21a: UV (ethanol) A,- 330,297,201, 194 nm; IR (KBr) v- 3451,3380,3030,3017,2942,2862,2790, 1676,1610,1497,1480,1466,1440,1381,1340,1305,1282,1244, 1207,1131,1104,1075,1044,744,700cm"; 270-MHz 'H NMR (CDC13) 6 0.77 (t, J = 7.3 Hz, 3 H), 0.88 (dd, J = 14.4, 4.0 Hz, 1H), 1.09-1.22 (m, 1 H), 1.40-1.55 (m, 2 H), 1.66 (dd, J = 11.0, 4.6 Hz, 1 H), 1.95-2.20 (m, 4 HI, 2.55-2.70 (m, 3 HI,2.77-2.89 (m, 1 H), 3.10 (8, 1H), 3.29-3.30 (m, 2 H), 3.77 (d, J = 14.0 Hz, 1H), 3.79 (s,3 H), 4.22 (d, J = 14.0 Hz, 1 H), 6.80-6.91 (m, 2 H), 7.01 (d, J = 7.7 Hz, 1 H), 7.22 (t, J = 7.7 Hz, 1HI, 7.31-7.48 (m, 5 H), 9.00 (br s, 1 H); 67.9-MHz 13C NMR (CDCl,) 8 8.01, 24.40, 28.88,34.12,36.60,42.77,50.89,55.22,58.30,60.59,67.31,74.20, 75.11, 91.09,109.22, 120.61, 122.11,127.00, 127.11, 128.22, 128.70, 138.01, 139.66, 143.21, 166.01, 168.92; mass spectrum, m/z (re1 intensity) 463 (38), 462 (M+,42) 431 (17), 374 (14), 373 (71), 330 (ll), 329 (55),320 (52), 249 (16), 248 (69), 241 (12), 328 (13), 234 (16), 228 (22), 215 (16),194 (ll),180 (14), 169 (17), 168 (21), 167 (20), 154 (27), 147 (18), 120 (21), 92 (16), 91 (loo), 57 (15). (3aR ,4R )-Methyl 3-Benzyl-2,3,3a,4,5,7-hexahydro-4[(2S)-2-ethyl-2-[(trimethylsilyl)oxy]-3-[(p-tolyl~ulfonyl)oxy]propyl]-lH-pyrrolo[2,3-~]carbazol~6-carboxylate (7a). A solution of 175 mg (0.38 mmol) of (3&,4R)-methyl3-benzyl2,3,3a,4,5,7-hexahydro-4[ (2S)-2-ethyl-2,3-dihydroxypropyl]-lHpyrrolo[2,3-d]carbazole-6-carboxylate(20a) and 106 pL (0.76 mmol) of triethylamine in 25 mL of dichloromethane was brought to 0 OC, and 247 mg (0.76 mmol) of p-toluenesulfonic anhydride
520 J. Org. Chem., Val. 56, No.2, 1991
Kuehne et al.
(1:4 ethyl acetate/pentanes); UV (ethanol) k- 208,282,311nm; was added. The reaction flask was purged with nitrogen, and the JR (KBr) v,, 3378,3050,3029,2965,2951,2885,2857,2830,2794, reaction mixture was stirred for 26 h. The reaction mixture was 1678,1611,1494,1478,1466,1453,1438,1366,1345,1303,1293, then washed with water, dried over magnesium sulfate, and 1281,1250,1203,1190,1177,1137,1102,1078,1051,1028,1019, concentrated under reduced pressure. Flash chromatography on 982,839,815,668,578,555,538,528,514cm-l; 250-MHz 'H NMR a 15 x 3.5 cm silica gel column, eluting with 1:l ether-hexane, (CDCl,) 6 0.10 (8, 9 H), 0.70 (t,J = 7.3 Hz, 3 H), 0.83 (dd, J = gave 177 mg (76%) of the primary alcohol tosylate: TLC R, 0.45 14,6,4.8 Hz, 1 H), 1.19 (dd, J = 14.5,4.6 Hz, 1H), 1.51-1.63 (m, 328, (silica gel, 4 1 ether-hexane, CAS blue); UV (ethanol) ,A, 2 H), 1.70 (dd, J = 11.8,4.4 Hz, 1 H), 2.03 (ddd, J = 11.8, 11.8, 295,223,202 nm; IR (KBr) u,, 3384,2928,2854,1678,1610,1496, 6.3 Hz, 1H), 2.20 (m, 1H), 2.44 (s,3 H), 2.61 (ddd, J = 13.6,8.1, 1477,1466,1438,1359,1304,1294,1281,1250,1204,1190,1178, 4.3 Hz, 1 H), 2.67 (m, 2 H), 2.91 (dd, J = 6.1, 8.8 Hz, 1H), 3.12 1129,1104,975,841,816,748,700,668cm-'; 270-MHz 'H NMR (s,1 H), 3.91 (d, J = 13.4 Hz, 1H), 3.71 (d, J = 9.5 Hz, 1H), 3.82 (CDCl,) 6 0.66 (t, J = 7.4 Hz, 3 H), 0.86 (dd, J = 14.7, 4.9 Hz, (d, J = 9.2 Hz, 1 H), 3.82 (s,3 H), 4.21 (d, J = 13.3 Hz, 1H), 6.88 1H), 1.10 (dd, J = 14.8, 6.1 Hz, 1H),1.26 (8, 1 H), 1.44 (q, J = (d, J = 7.7 Hz, 1 H), 6.93 (t, J = 7.4 Hz, 1H), 7.14 (d, J = 7.3 14.7, 7.2 Hz, 2 H), 1.64 (dd, J = 11.7,4.4 Hz, 1H), 1.76 (s, 1H), Hz, 1 H), 7.21 (t, J = 7.7 Hz, 1H), 7.30-7.45 (m, 5 H), 7.31 (d, 1.92-2.09 (m, 1 H), 2.39 (s, 3 H), 2.53-2.59 (br s, 3 H), 2.85-2.91 J = 7.9 Hz, 2 H), 7.76 (d, J = 8.2 Hz, 2 HI, 9.03 (br s, 1 H); (m, 1 H), 3.03 (9, 1 H), 3.64-3.76 (m, 3 H), 3.77 (s,3 H), 4.12 (d, 67.9-MH~'3C N M R (CDClS) 6 2.43,8.01,21.42,24.72,29.54,33.59, J = 13.6 Hz, 1H), 6.80-6.87 (m, 2 H), 7.00 (d, J = 7.4 Hz, 1H), 37.57,43.05, 50.67, 50.71, 55.07,58.36, 73.23, 74.37, 77.74,91.43, 7.15 (t, J = 7.4 Hz, 1 H), 7.24-7.40 (m, 7 H), 7.72 (d, J = 8.2 Hz, 109.10,120.55,122.09,126.89,127.72,127.86,128.22,129.67,132.98, 2 H), 8.89 (8, 1H); mass spectrum, m/z (re1 intensity) 446 (13), 137.76, 139.51, 142.99, 144.63, 165.84, 168.97. 445 (55),444 (1001,427 (lo), 426 (131,413 (81,353 (141,312 (71, ( 7 s ,5R )-Methyl 3-Benzyl- 1,2,3,4,5,6,7,8-octahydro-5311 (26), 292 (51,279 (111,278 (171,261 (51,246 (51,238 (61,231 [(2S)-2-ethyl-2-[(trimethylsilyl)oxy]-3-[(p-tolylsulfonyl)(7), 230 (50),227 (5),226 (9,200 (5),173 (61, 172 (13), 155 (12), oxylpropyll-7-( 15-vindolinyl)azonino[ 5,4-b ]indole-7140 (12), 139 (41), 134 (6), 124 (7), 123 (17), 107 (12), 106 (9), 105 of carboxylate (27a). A solution of 0.10 g (0.14 "01) (8), 92 (19), 91 (781, 86 (181, 77 (13),65 (10). (3aR,4R)-methyl 3-benzyl-2,3,3a,4,5,7-hexahydro-4-[(2S)-2A solution of 150 mg (0.32 mmol) of (3aR,4R)-methyl 3ethyl-2-[(trimethylsilyl)oxy]-3-[@-tolylsulfonyl)oxy]propyl]-1Hbenzyl-2,3,3a,4,5,7-hexahydro-4[ (2S)-2-ethyl-2-hydroxy-3[( p pyrrolo[2,3-d]carbazole-6-carboxylate(7a) and 21 pL (1.1 equiv) tolylsulfonyl)oxy]prpyl]-lH-pyrrolo[ 2,3-d]carble~carboxylate of triethylamine in 5 mL of dichloromethane was stirred under and 64 p L (1.5 equiv) of NJV-diisopropylethylaminein 25 mL of nitrogen and brought to 0 "C. Dropwise addition of 19 p L (1.1 tetrahydrofuran was stirred under nitrogen and brought to 0 "C, equiv) of tert-butyl hypochlorite in 2 mL of dichloromethane and and 71 pL (1.5 equiv) of trimethylsilyl trifluoromethanesulfonate stirring for 5 min gave a solution, which by TLC was free of was added by syringe. The solution was stirred for 15 min, then starting compound (CAS blue) and which contained a new, less washed with 15 mL of aqueous saturated sodium bicarbonate, polar chlorination product (23a), R, 0.6 (2:3 hexane-ether, CAS dried over magnesium sulfate, and concentrated under reduced purple). The solution was washed with 2 X 5 mL of water, dried pressure. Flash chromatography on a 12.5 X 3.5 cm silica gel over magnesium sulfate, and concentrated under vacuum to give column, eluting with 1:lethelchexane, gave 154 mg (92%) of the a white foam, which was used in the next reaction. title product as a white foam: TLC Rr 0.37 (silica gel, 1:l ethTo a solution of the chlorination product 23a and 0.063 g (0.95 er-hexane, CAS blue green); UV (ethanol) A, 327,296,223,199 equiv) of vindoline (3) in 5 mL of dry acetone, was added 47 pL nm; IR (KBr) u- 3383,3060,3030,2951,2857,2790,1678,1610, (2 equiv) of tetrafluoroboric acid-diethyl ether complex. After 1496,1478,1466,1438,1365,1345,1304,1294,1281,1250,1202, 1190,1178,1136,1101,1078,1052,1028,1018,982,838,814,746,5 min, 0.056 g (2 equiv) of silver tetrduoroborate in 2 mL of dry acetone was added, causing the mixture to become heterogeneous. 700, 666, 554 cm-'; 270-MHz 'H NMR (CDClJ 6 0.03 (s,9 H), After 5 min, TLC showed no remaining starting material. Ad0.63 (t, J = 7.4 Hz,3 H), 0.75 (dd, J = 14.6,4.6 Hz, 1H), 1.10-1.16 dition of 10 mL of 10% aqueous ammonium hydroxide, extraction (dd, 1 H), 1.48-1.67 (m, 4 H), 1.9-2.12 (m, 2 H), 2.39 (8, 3 H), with 4 X 15 mL of dichloromethane, drying (MgSO,), and con2.49-2.60 (m, 3 H), 2.81-2.88 (m, 1 H), 3.05 (9, 1 H), 3.55-3.73 centration under vacuum gave a white foam. (m, 2 H), 3.76 (s, 3 H), 4.15 (d, J = 13.4 Hz, 1 H), 6.80-6.87 (m, This material, 25a, was dissolved in 10 mL of acetic acid and, 2 H), 7.07 (d, J = 7.3 Hz, 1H), 7.16 (t, J = 7.5 Hz, 1H), 7.24-7.39 with stirring, 0.078 g (10 equiv) of potassium borohydride was (m, 7 H), 7.70 (d, J = 8.2 Hz, 2 H), 8.94 (br s, 1 HI; 67.9-MHz slowly added. After being stirred for 10 min, the reaction mixture 13CNMR (CDCl,) 6 169.0,166.0, 144.7,143.0,139.6, 137.8, 133.0, was poured onto ice and made strongly basic with concentrated 129.8, 129.7,128.6,128.2,127.9, 127.7, 126.9, 122.1,120.5,109.1, ammonium hydroxide. Extraction with 4 X 15 mL of dichloro91.4, 77.7, 74.2, 73.6, 58.4, 55.0, 50.8, 43.0, 37.6, 33.8, 29.7, 24.7, methane, drying (MgSO,), and concentration under vacuum gave 21.5,8.1,2.4; mass spectrum, m/z (re1 intensity) 688 (M', 9), 503 a white foam. Flash chromatographyon silica, eluting with ethyl (4), 475 (5),474 (22),374 (21), 373 (loo), 332 (6), 229 (7), 228 (16), acetate, gave 0.126 g (80% based on vindoline) of the title product 210 (a), 207 (5),194 (4), 180 (4), 168 (9), 167 (5),155 (5),92 (7), In some experiments only 65-70% yields were obtained, possibly 91 (78), 86 (5),75 (6), 73 (22). (3aS,4S)-Methyl 3-benzyl-2,3,3a,4,5,7-hexahydro-4- due to cleavage of the silyl ether by fluoride: TLC R, 0.61 (ethyl acetate, CAS dark brown-purple); UV 1s,296,288,262,215,202 [(29)-2-ethyl-2-[(trimethylsilyl)oxy]-3-[( p-tolylsulfonyl)nm;IR (KBr) u,, 3500,3445,3048,2970,2900,2820,1756,1732, oxy]propyl]-lEI-pyrrolo[2,3-d]carbazole-6-carboxylate (22a) 1625,1608,1512,1474,1445,1376,1350,1309,1260,1238,1202, was prepared by the above procedure from the diol 21a in 88% 1190,1075,1054,990,851,753,710,682,568cm-'; 270-MHz 'H yield. For the initial intermediate tosylate alcohol: UV (ethanol) NMR (CDC13) 6 0.0 ( ~ , H), 9 0.58 (t, J = 7.1 Hz, 3 H), 0.92 (t, J 1s,205,283,311nm; IR (KBr) u- 3393,3103,3084,3056,3029, = 6.8 Hz, 3 H), 1.10-1.47 (m, 6 H), 1.81-1.92 (m, 3 H), 2.18 (8, 2970,2943,2891,2855,1674,1609,1478,1465,1438,1360,1303, 1294,1280,1250,1203,1190,1177,1133,1102,1078,1051,1028, 3 HI, 2.18-2.45 (m, 4 HI, 2.40 (s,3 HI, 2.66 (s,2 H),2.80 (s,3 H), 3.05-3.44 (m, 6 H),3.67 (8, 3 H), 3.50-3.79 (m, 6 H),3.84-3.91 1019,974,841,814,737,701,668cm-';250-MHz 'H NMR (CDCl,) (m, 6 HI, 5.37 (d, J = 10.1 Hz,1 H), 5.57 (a, 1 H), 5.91 (dd, J = 6 0.69 (t, J = 7.4 Hz, 3 H), 0.82 (dd, J = 14.7,4.9 Hz, 1 H), 1.08 10.1,4.0Hz, 1H), 6.26 ( ~ H), , l 6.84 ( 8 , l H), 6.84 ( ~ ,H), l 7.07-7.48 (dd, J = 14.8,5.3 Hz, 1H),1.26-1.57 (m, 2 H), 1.62 (dd, J = 11.7, (m, 11 H),7.75 (d, J = 8.2 Hz, 2 H), 8.07 (br s, 1 H), 9.98 (br s, 4.3 Hz, 1 H), 1.90 (m, 1 H), 1.98 (ddd, J = 11.9, 11.9,6.2 Hz, 1 1H); 67.9-MH~'3C NMR 6 174.5, 171.6, 170.6,157.8, 152.9, 144.5, H),2.13 (m, 1 HI, 2.38 (e, 3 H), 2.52-2.65 (m, 3 HI, 2.87 (dd, J 140.2, 134.8, 133.2, 131.8, 129.9, 129.5, 129.2, 127.9, 127.8, 127.6, = 8.5,6.6 Hz, 1 H),3.09 (a, 1H), 3.64 (d, J = 11.0 Hz, 1H), 3.69 126.3, 124.4, 124.1, 123.2, 121.9, 121.3, 118.7, 117.9, 115.4, 110.1, (d, J = 13.5 Hz, 1 H), 3.75 (8, 3 H), 3.72 (d, J = 11.9 Hz, 1 H), 94.1, 83.3, 79.5, 77.4, 76.4, 72.8, 66.0, 64.5, 58.5, 55.8, 55.5, 53.5, 4.15 (d, J = 13.5 Hz,1 H), 6.80 (d, J = 7.7 Hz, 1 H), 6.83 (t, J = 7.6 Hz, 1 H), 6.95 (d, J = 6.8 Hz, 1 H), 7.13 (t, J = 7.9 Hz, 1 53.1, 51.9, 51.8, 50.2, 44.4, 42.7, 41.0, 38.1, 37.3, 32.6, 30.7, 29.5, 25.6, 21.3, 20.8, 8.37, 5.23. H), 7.23-7.45 (m, 5 H),7.26 (d, J = 8.2 Hz, 2 H), 7.69 (d, J = 8.2 (7R ,5S )-Methyl 3-Benzyl-1,2,3,4,5,6,7,8-octahydro-5Hz,2 H), 8.90 (br s, 1 H); 67.9-MHz 13C NMR (CDCl,) 6 7.69, 21.44, 24.52, 29.10, 33.64, 36.28, 42.64, 50.55,58.04, 73.78, 73.83, [(25)-2-ethyl-2-[(trimethylsilyl)oxy]-3-[( p-tolylsulfonyl)91.02,109.13,120.61,122.15,126.94,127.74, 127.82, 128.21,128.84, oxy]propyl]-7-(15-vindolin~l)azonino[S,4-b ]indole-7carboxylate (28a). This compound was prepared by the pro129.77, 132.79, 137.71,139.20, 142.90, 144.76, 165.42, 168.85. For 22a: TLC R, (silica gel) (1:l ether-hexane, CAS blue-green) 0.54 cedure (CDC13)for preparation of its diastereomer 27a, providing
J. Org. Chem., Vol. 56,No.2, 1991 521
Enantioselective Syntheses of Binary Alkaloids
1154, 1145, 1127, 1108, 1092, 1042, 1O00, 962, 817, 739 cm-'; the title product in 78% yield and 10% of ita desilylation product 270-MH~'H NMR (CDCl,) 6 0.47 (t, J = 6.8 Hz, 3 H), 0.72 (t, from the coupling of vindoline to the silyl tosylate 22a after J = 7.1 Hz, 3 H), 0.91-1.02 (m, 1H), 1.05-1.28 (m, 3 H), 1.29-1.41 centrifugal chromatography (silica gel, ethyl acetate): TLC R (m, 1 H), 1.50-1.73 (m, 2 H), 1.73-1.89 (m, 1 H), 2.06 (8, 3 H), 0.50 (silica gel, ethyl acetate, CAS dark brown-purple); Utf 2.13-2.72 (m, 14 H), 2.76 (s,3 H), 2.86-2.99 (m, 1 H), 3.05-3.19 (ethanol) A, 297,288,257,221,212,196 nm; IR(KBr) Y- 3415, (m, 2 H), 3.28-3.52 (m, 4 H), 3.55 (8, 3 H), 3.65 (t, J = 10.9 Hz, 3028,2950,2911,2893,2878,2838,2803,2748,1742,1615,1598, 1497,1461,1432,1412,1368,1338,1321,1297,1249,1225,1190, 1 H), 3.80 (s, 6 H), 5.28 (d, J = 9.1 Hz, 1 H), 5.44 (8, 1 H), 5.85 1177,1151,1131,1121,1109,1097,1064,1042,1001,978,840,740, (dd, J = 9.4,4.6 Hz, 1 H), 6.13 (8, 1 H), 6.88 (br s, 1H), 7.00-7.34 (m, 8 H), 7.43 (d, J = 7.6 Hz, 1H), 8.05 (br s, 1 H), 9.79 (br s, 667 cm-'; 270-MHz 'H NMR (CDC13)6 0.06 (s, 9 H), 0.43 (br t, 1H);67.9-MHz '% NMR (CDC13)6 7.87,8.07, 20.87, 25.52,26.29, J = 7.2 Hz, 3 H), 0.56 (br t, J = 7.7 Hz, 3 H), 1.09-1.51 (m, 4 H), 30.44, 32.33, 34.43, 38.53, 39.02,42.20, 45.55, 50.18, 52.04, 52.12, 1.60-1.91 (m, 2 H), 2.06-3.21 (m, 11 H), 2.12 (8, 3 H), 2.49 (8, 3 53.41,53.94,55.24, 55.42,57.54,58.81,64.88,65.72,75.80,79.58, H), 2.75 (8, 3 H),3.22-3.94 (m, 10 H), 3.85 (8, 6 H), 3.63 (8, 3 H), 83.55,93.38,110.04, 115.83, 118.11, 118.84, 121.03, 122.04, 123.19, 5.30 (d, J = 10.8 Hz, 1 H), 5.54 (8, 1 H), 5.86 (dd, J = 10.9, 4.3 124,03,126.53,127.99,128.13,128.98,129.93,131.65,134.75,139.93, Hz, 1 H), 6.07 ( 8 , 1 H), 6.86 (8, 1 H), 7.05-7.60 (m, 12 H), 7.83 153.04,158.13,170.34,171.46,174.29;mass spectrum,m/z (relative (d, J = 7.2 Hz, 1 H), 8.13 (8, 1 H), 9.74 (8, 1 H); '3C NMR (CDClg) 6 2.34,7.93,8.15,20.90,21.48,26.07,29.99,30.52,33.31,38.39,39.82,intensity) 901 (42), 900 (M+,72) 842 (6), 811 (lo), 810 (19), 809 (lo), 751 (9), 741 (9), 741 (9), 617 (lo), 540 (8) 527 (9), 470 (lo), 42.74,44.67, 50.50, 51.02, 52.09, 52.17, 53.19,53.80, 55.55, 57.89, 64.59,66.32,73.52,76.64,79.41,83.46,94.35,110.11,117.95,118.55, 469 (26), 444 (6), 432 (23), 431 (73), 413 (6), 409 (7), 380 (a), 355 121.79,123.56,124.04,126.51,127.79, 128.00,128.09,129.72,130.02, (ll), 341 (6), 295 (7), 282 (24), 273 (6), 272 (6), 261 (lo), 231 (la), 230 (loo), 222 (lo), 218 (9), 217 (29), 214 (9), 212 (13), 202 (lo), 133.16,134.62,140.24, 144.39,152.93,158.21,170.40, 171.71,175.22. (75,5R)-Methyl 3-Benzyl-1,2,3,4,5,6,7,8-octahydro-5- 200 (lo), 188 (lo), 174 (6), 154 (27), 144 (8),136 (13). 135 (49), 134 (16), 122 (25), 121 (20), 120 (7), 109 (81,107 (19), 106 (6), 93 [(25)-2-ethyl-2,3-epoxypropyl1-7-( 15-vindoliny1)azonino(ll),92 (12), 91 (70), high resolution mass spectrum (EI, mass [5,4-b]indole-7-carboxylate(31a). To a solution of 0.07 g (0.06 mmol) of (7S,BR)-methyl 3-benzyl-1,2,3,4,5,6,7,8-octahydro-5- resolution 12000), M calcd 900.46729, found 900.47003. Anal. Calcd for C63&NIOgCHs0H C, 69.51; H, 7.35; N, 6.00. Found [ (2S)-2-ethyl-2-[(trimethylsilyl)oxy]-3-(p-tolylsulfonyl)oxy]C, 69.41; H, 7.21; N, 5.86. The sample was obtained by centrifugal propyl]-7-(15-vindolinyl)azonino[5,4-b]indole-7-carboxylate (27a) chromatography on silica gel with 5% methanol in dichloroin 20 mL of tetrahydrofuran was added 0.184 mL (3 equiv, 1M methane. It showed methanol signals in the NMR spectnun after in THF) of tetrabutylammonium fluoride. After 25 min, TLC drying under high vacuum. showed complete conversion of starting material to a more polar Vinblastine (1) and Its 17'-Equatorial Conformational product. The reaction mixture was washed with aqueous saturated of (7S,5R)-methyl Isomer 30. A solution of 0.040 g (0.044 "01) sodium bicarbonate, dried (MgSO,), and concentrated under 3-benzyl-1,2,3,4,5,6,7,8-octahydro-5-[ (2S)-2-ethyl-2,3-epoxyvacuum. Flash chromatography on silica, eluting with ethyl (31a) propyl]-7-(15-vindolinyl)azonino[5,4-b]indole-7-carboxylate acetate, gave 0.047 g (85% yield) of the title compound: TLC in 10 mL of methanol was heated at reflux for 26 h, at which time Rf 0.33 (silica gel, ethyl acetate, CAS brown); UV (ethanol) X, TLC showed no remaining starting material and a new more polar 296,289,258,215,201 nm; IR (KBr) um, 3466,3030,2970,2934, product (Rf0.25,2% triethylamine in methanol, CAS blue): UV 2878,2802,1744,1704,1612,1502,1460,1432,1371,1336,1296, (ethanol) A,- 292,266,216nm. The reaction mixture was cooled 1226,1172,1146,1042,957,886,818,740,701,480cm-'; 270.MHz and flushed with nitrogen and 20 mg of 10% Pd on charcoal was 'H NMR (CDClg) 6 0.54 (t,J = 7.2 Hz, 3 H), 0.85 (t,J = 7.2 Hz, added. This was stirred under a hydrogen atmosphere at room 3 H), 0.98-1.81 (m, 12 H), 1.95-2.04 (m, 1 H), 2.10 (s, 3 H), temperature for 2 h, filtered, and concentrated under vacuum. 2.15-2.17 (m, 1 H), 2.28-2.62 (m, 6 H),2.66 ( 8 , 3 H), 2.73-3.34 Flash chromatography on a 22 X 12 cm silica gel column, eluting (m, 3 H), 3.63-3.64 (m, 6 H), 3.77-3.82 (m, 8 H), 5.30 (d, J = 10.4 with 1% triethylamine in methanol, gave 0.032 g (89%) of the Hz, 1 H), 5.44 (s, 1 H), 5.81 (dd, J = 10.3, 4.0 Hz, 1 H), 6.12 (s, 17'-equatorial conformational isomer 30 of vinblastine as a white 1H), 6.73-6.80 (m, 3 H), 6.83-7.01 (m, 3 HI, 7.11-7.20 (m, 2 HI, solid. This compound crystallized to provide a sample with mp 7.36 (d, J = 7.7 Hz,1H), 8.06 (br 8, 1H), 9.81 (br 8, 1H); 67.9-MHz 210-213 "C, with gradual change of particles at 80-120 "C (vin"C NMR (CDClg) 6 8.17, 8.37, 20.74, 25.06, 26.58, 30.61, 32.93, blastine lit.% mp 211-216 "C): TLC R 0.23 (silica gel, 1%tri37.83, 38.32, 39.86, 42.54, 44.45,49.36,49.78, 51.74, 51.92, 52.02, (ethanol) A,- 292,261, ethylamine in methanol, CAS purple); 52.81,53.01, 55.57,56.27, 58.11,60.30,62.86,65.30,76.24, 79.47, 222,216,205 nm; IR (KBr) u,, 3406,3389,2953,2935,2877,2808, 83.42,94.01, 110.08, 114.37, 117.88,118.66, 121.73, 122.05, 122.93, 124.14,125.38,126.14,127.43,127.71,129.18,129.85,132.23,134.77, 1738,1616,1594,1499,1459,1433,1372,1331,1300,1246,1145, 1086, 1040, 1012, 744 cm-'; 250-MHz 'H NMR (CDClS) [Most 139.78, 152.62,158.01,170.41, 171.34, 174.51; high resolution mass signals in this spectrum were very broad and complex due to the spectrum (EI, direct probe, mass resolution 12000), calcd for presence of three or more conformers, precluding meaningful CS3HuN4O9900.46729, found 900.46909; mass spectrum,m/z (re1 analysis and integration. The observed signals were classified intensity) 901 (lo), 900 (M+,17),841 (6), 788 (61,742 (6), 741 (lo), as broad "singlets" (br s) or sharp singlet (s)] (br 8 ) 6 10.78,9.74, 650 (7), 649 (13), 566 (6), 540 (61, 527 (81,469 (91, 444 (a), 431 9.69, 9.46, 9.41, 9.12, 8.98, 8.59, 6.01, 5.93, 5.75, 5.37, 5.23, 5.10, (lo), 380 (7), 373 (9), 355 (6), 295 (61, 282 (181, 273 (71, 272 (7), 0.18; ( 8 ) 6 3.79, 3.76, 3.74, 3.73, 3.57, 2.29, 2.02; multiplets 6 262 (6), 261 (21), 260 (7), 259 (a), 258 (7), 244 (a), 231 (6), 230 7.35-6.74,0.88; mass spectrum, m/z (re1intensity) 825 (M+ + 15, (30), 222 (8),218 (9), 217 (9), 214 (7), 212 (6), 202 (a), 200 (7), 188 13), 8.24 (25), 811 (17), 810 (M', 32), 809 (9), 808 (91, 780 (111, (ll), 174 (6), 169 (6), 168 (9), 154 (lo), 144 (12), 143 (lo), 136 (141, 779 (16), 767 (7), 766 (12), 753 (151, 752 (33), 751 (23), 750 (ll), 135 (53), 134 (19), 130 (7), 124 (6), 122 (231, 121 (21), 120 (a), 108 749 (6), 732 (5),652 (6), 651 (ll),650 (a), 649 (9), 612 (6), 610 (9), 107 (22), 106 (a), 93 (12), 92 (19),91 (100),79 (6), 77 (61, 65 (6), 593 (5),591 (5),571 (7), 543 (9), 527 (5),470 (7), 469 (17), 381 (17),60 (7),55 (7), 51 (6). Anal. Calcd for CSsHuNIOgCH30H (6), 356 (7), 355 (21), 354 (6), 353 (71,343 (51,341 (6), 327 (5),325 C, 69.51; H, 7.35; N, 6.00. Found 69.35; H, 7.49; N, 6.22. The (5), 313 (5),311 (5),297 (6), 296 (5), 295 (9), 283 (a), 282 (22), 272 analytical sample was obtained by centrifugal chromatography (6),268 (6), 240 (5),222 (7), 214 (a), 202 (a), 200 (a), 188 (12), 186 on silica gel with 5 % methanol in dichloromethane. It showed (6), 183 (5),174 (6), 172 (6), 171 (5), 168 (6), 156 (7), 155 (12), 154 methanol signals in the NMR spectrum after drying under high (loo),144 (lo), 141 (13), 140 (ll), 136 (211,135 (52), 130 (6), 124 vacuum. (7R,55)-Methyl 3-Benzyl-1,2,3,4,5,6,7,8-octahydro-5- (16), 123 (8),122 (30), 121 (25), 108 (lo), 107 (211, 106 (7), 100 (6),93 (12), 92 (6),91 (5), 83 (131, 82 (9), 81 (6),70 (lo), 58 (21); [(2S)-2-ethyl-2,3-epoxypropylI-7-( 15-vindo1inyl)azoninohigh resolution mass spectrum (EI), M calcd 810.4203801,found [5,4-b]indole-7-carboxyIat.e(33a). Following the procedure for 810.417W, CD (0.032 mg/mL methanol), h (ellipticity)214 (-177), preparation of the diastereomer 31a, the 0-silyl tosylate 28a 225 (4), 258 (53), (0.32 mg/mL) 307 (-13). provided the centrifugally chromatographed (silica gel, ethyl This product was dissolved in toluene and heated at reflux for acetate) product in 93% yield: TLC (silica gel) R 0 35 (ethyl 8 h, at which time TLC showed no remaining starting material acetate, CAS brown), 0.69 (5% methanol in CH2C1,); (ethanol) A, 199,212, 248,270,282,287 nm; IR (KBr) u,, 3459,3057, 3028,2964,2943,2935,2879,2856,2838,2802,2797,1742,1615, (25) News, N.; Gorman, M.; Svoboda, G. H.; Maciak, G.; Beer, C. T. 1595,1500,1460,1432,1370,1336,1321,1298,1244,1227,1172,J. Am. Chem. Sac. 1959,81,4754.
ut
h
522 J . Org. Chem., Vol. 56, No. 2, 1991
Kuehne et al.
136 (36), 135 (49), 134 (6), 130 (14), 124 (14), 123 (131,122 (331, and a new less polar product, which chromatographicallymatched 121 (31), 110 (6), 108 (16), 107 (481,106 (321,105 (5), 94 (6),93 an authentic sample of vinblastine. Concentration of the solvent (12), 92 (36), 91 (20), 84 (ll),82 (lo), 81 (6), 80 (5), 79 (ll), 77 and flash chromatography, eluting with 5:1:0.01 ether-acetone(11),70 (lo), 67 (7), 65 (12), 60 (19), 59 (81,58 (93), 57 (9); high triethylamine, gave 0.03 g (95% yield) of vinblastine: TLC R, resolution mass spectrum (EI), M calcd 810.4203801, found 0.36 (silica gel, 5% methanol in dichloromethane, CAS violet); 810.423035; CD (0.021mg/mL methanol) X (ellipticity) 210 (44.5), IR (KBr) u,, 3466,3027,2957,2948,2878,2852,2815,1741,1616, 224 (-145.5), 261 (+23.0), (0.21 mg/mL) 309 (10.9). On heating 1502,1460,1433,1371,1332,1295,1243,1228,1193,1145,1130, in toluene at reflux for 2 h the atropisomer 35a was converted 1109,1094,1080,1040,1009,742cm-'; 270-MHz 'H NMR (CDCl,) to 2(Y-epi-vincovaline(14a) in 90% yield TLC (silica gel) R 0.36 6 0.82 (t, J = 6.8 Hz, 3 H), 0.88 (t, J = 7.4 Hz, 3 H), 1.30-1.48 (10% methanol in CHQ,), 0.31 (100:5:5:5 etherlmethanorjtol(m, 4-5 H), 1.78-1.86 (m, 2 H), 2.12 (s, 3 H), 2.19-2.47 (m, 3-4 uene/diethylamine); HPLC (under conditions given for 35a) t~ H), 2.67-2.69 (m, 1H), 2.81 (s, 3 H), 2.81-2.87 (m, 3 H), 3.10-3.20 2.5 min; UV (ethanol) A, 211,221, 253,291,302 nm; IR (KBr) (m,2 H), 3.25-3.41 (m, 4 H), 3.62 (s, 3 H), 3.68-3.74 (m, 2 H), v,, 3413, 3029, 3022, 2964, 2953, 2878, 2852, 2841, 2810,2740, 3.80 (s, 6 H), 3.87-4.00 (m, 1 H), 5.30 (d, J = 9.9 Hz, 1 H), 5.46 1739,1616,1501,1460,1432,1371,1334,1296,1244,1226,1172, (s, 1 H), 5.85 (dd, J = 9.2, 3.7 Hz, 1 H), 6.10 (s, 1 H), 6.61 (8, 1 1156,1146,1120,1108,1093,1038,1003,739 cm-'; 270-MHz 'H H), 7.13-7.26 (m, 3 H), 7.52 (d, J = 7.5, 1 H), 8.03 (s, 1 H), 9.90 NMR (CDC13) 6 0.41 (t, J = 7.2 Hz, 3 H), 0.96 (t, J = 7.1 Hz, 3 (br s, 1H); 67.9-MHz 13C NMR (CDClJ 6 174.58, 171.43, 170.48, H), 0.96-1.08 (m, 2 H), 1.23-1.38 (m, 3 H), 1.55-1.80 (m, 5 H), 157.90,152.40,134.73,131.17,129.77,129.20,124.15,123.35,122.64, 1.80-1.86 (m, 1H), 2.66 (8, 3 H), 2.09-2.38 (m, 2 H), 2.43 (m, 2 121.91, 120.98, 118.54, 118.15, 116.62, 110.09, 93.99, 83.16, 79.36, H), 2.74 (s, 3 H), 2.79-2.86 (m, 2 H), 3.05-3.74 (m, 5 H), 3.55 (8, 76.20, 69.12,65.58, 64.02, 55.53, 52.96, 51.95, 51.81, 50.25, 50.09, 3 H), 3.80 (s, 3 H), 3.81 (s, 3 H), 5.22 (d, J = 10.5 Hz, 1 H), 5.46 47.81,44.25,42.49,41.06,38.05,34.12, 30.55, 29.85,28.19, 28.14, (8, 1 H), 5.80 (dd, J = 4.5, 10.5 Hz, 1 H), 6.16 (e, 1 H), 6.66 (8, 20.75,8.06,6.63; mass spectrum, m/z (re1 intensity) 825 (M + 15, 1 H), 7.14-7.25 (m, 4 H), 7.49 (d, J = 7.8 Hz, 1 H), 8.09 (br s, 1 21), 824 (41), 811 (M++ 1, 19), 810 (M+,371,809 (lo), 808 (13), H), 9.61 (br s, 1H); 67.9-MHz '3c NMR (CDCld 6 6.80,8.05,20.25, 780 (9), 779 (16), 767 (7), 753 (ll),752 (26), 751 (23), 720 (17), 20.76, 27.64, 30.67, 34.49, 38.16, 38.68, 39.94,42.52,44.01, 44.51, 734 (7), 652 (51, 651 (121, 650 (81, 649 (91, 571 (71, 543 (81, 525 50.25, 52.20, 53.10, 53.46, 54.34, 55.14, 55.43, 66.61, 70.48, 75.69, (5), 470 (6), 469 (141, 381 (5), 356 (91,355 (32), 354 (61, 353 (61, 79.22,83.37, 94.07, 110.27, 144.45, 117.72, 119.10, 119.45, 122.71, 325 (5), 296 (51, 295 (81,283 (61, 282 (231, 272 (6), 268 (61, 240 123.22,123.82,123.86,128.16,129.56,130.63,134.76,153.32,157.79, (5), 222 (6), 214 (6), 202 (6), 200 (7), 188 (lo), 174 (6), 170 (6), 168 170.37,171.52,173.52; high resolution mass spectrum (EI, mass (5), 156 (6), 155 (12), 154 (loo), 144 (lo), 142 (5), 141 (13), 140 resolution 12 000), M calcd 810.423801, found 810.41498; mass ( l l ) , 136 (22), 135 (51), 130 (5), 124 (le), 122 (29), 121 (24), 108 spectrum m/z (relative intensity) 838 (lo), 825 (20), 824 (37), 810 (lo), 107 (191, 106 (7),93 (12), 84 (7),83 (11),82 (7),81 (51, 70 (M+,8))792 (12), 766 (ll),752 (ll),735 (6), 734 (10),612 (6), 591 (a), 58 (24); high resolution mass spectrum (EI), M calcd (6),516 (a), 502 (8),500 (31), 499 (7), 369 (a), 356 (6), 297 (5), 295 810.4203801, found 810.417114; CD (0.027 mg/mL ethanol) X (7), 294 (6), 283 (7), 282 (23), 222 (a), 214 (81,202 (81,200 (e), 188 (ellipticity) 214 (-383), 225 (138), 258 (84), (0.250 mg/mL) 303 (lo), 174 (6), 170 (6), 168 (6), 156 (7), 155 (ll),154 (100), 144 (11)) (20). 141 (21), 140 (14), 136 (29), 135 (57), 130 (7), 124 (16), 123 (a), 20'-epi-Vincovaline (14a) and Its Atropisomer 35a. Fol122 (33), 121 (28), 108 (12), 107 (221, 106 (8),93 (13),92 (7),91 lowing the procedure for the preparation of vinblastine but with (81,84 (9), 83 (a), 82 (81, 81 (6), 70 (ah60 (6), 58 (41); CD (0.026 addition of 1.5 equiv of acetic acid to 0.206 g of the epoxide 33a mg/mL methanol) X (ellipticity)211 (102.5),222 (-189.5), 258-260 in 10 mL of methanol and heating at reflux for 48 h, and with (20), (0.29 mg/mL) 304 (-21.0). centrifugal chromatography (silica gel, 100:5:5:5 ether/toluVinblastine 20'-Trimethylsilyl Ether. A solution of 0.070 ene/methanol/triethylamine), the atropisomer 35a of 20'-epig (0.061 mmol) of (7S,5R)-methyl 3-benzyl-l,2,3,4,5,6,7&octavincovaline was obtained from the epoxide 33a in 97% yield TLC hydro-5- [ (2S)-2-ethyl-2-[ (trimethylsilyl)oxy]-3-[ (p-tolylR, 0.017 (100555 ether/toluene/methanol/diethylamine),R, 0.24 sulfonyl)oxy]propyl]-7-(15-vindolinyl)azonino[5,4blindole-7(1W1 methanol/triethylamine); HPLC t R 3.41 min (80201 carboxylate (27a) in 10 mL of methanol was heated at reflux under methanol/water/triethylamine,4.6 X 100 mm Rainin microsorb nitrogen for 40 h, at which time TLC showed no remaining starting C-18 3 r m (100 A) column at 1 mL/min, detection at 260 nm); material and a new, more polar product (R, 0.38,2% triethylamine UV (ethanol) A, 204,214,254,278,285,300nm; IR (KBr) vin methanol, CAS brown). The reaction mixture was cooled to 3403,3088,3077,3037,3032,3016,2961,2935,2930,2878,2848, 2812,2734,2721,2690,1743,1718,1617,1597,1499,1488,1459, room temperature and flushed with nitrogen, and 0.010 g of 10% 1431,1371,1332,1302,1247,1236,1190,1170,1150,1129,1118, palladium on carbon was added. The mixture was stirred under a hydrogen atmosphere for 2 h. TLC then showed complete 1098, 1068, 1042, 1020, 968, 946, 911, 982, 737, 712, 621 cm-'; conversion of starting material to a less polar compound (TLC 270-MHz 'H NMR (CDCls) S 0.57 (t,J 6.8 Hz, 3 H), 0.80-1.02 R, 0.36, 5% methanol in dichloromethane, CAS purple). The (m, 1 H), 0.95 (br t, J = 7.2, 3 H), 1.05-1.31 (m, 3 H), 1.34-1.51 reaction mixture was filtered, the filtrate was washed with di(m, 4 H), 1.62-1.75 (m, 1 H), 1.90-2.09 (m, 3 H), 2.07 (8, 3 H), chloromethane, and the combined solvents were concentrated 2.22-2.40 (m, 1H), 2.42-3.04 (m, 6 H), 2.66 (br s, 3 H), 3.10-3.24 under vacuum. Flash chromatography on silica gel eluting with (m, 3 H), 3.32-3.62 (m, 1H), 3.55 (br s, 3 H), 3.78 (s,6 H), 5.26 5% methanol in dichloromethane gave 0.048 g (90%) of the title (d, J = 9.1 Hz,1H), 5.44 (8, 1H), 5.88 (dd, J = 4.4,9.2 Hz, 1H), compound 270-MHz 'H NMR (CDCl,) 6 0.28 (s,9 H), 0.78-0.88 5.94 (br s, 1 H), 6.95-7.30 (m, 4 H), 7.37 (d, J = 7 Hz, 1H), 9.52 (m, 6 H), 1.21-1.88 (m, 10 H), 2.10 (8, 3 H), 2.15-2.30 (m, 1 H), NMR (CDC13 6 7.05, (br s , 1 H), 10.93 (br s, 1 H); 67.9-MHz 2.39-2.48 (m, 2 H), 2.68 (8, 1H), 2.70 (e, 3 H), 2.76-2.90 (m,3 H), 7.53, 20.91, 26.58, 28.20, 30.49, 34.01, 35.96, 38.22, 42.83, 43.11, 3.04-3.40 (m, 5 H), 3.62 (s,3 H), 3.72 (8, 1HI, 3.79 (s,3 H), 3.80 43.33,51.17,52.04, 52.21, 52.33,53.22,53.57,53.90,54.43, 55.84, (s, 3 H), 3.84-4.06 (m, 2 H), 5.29 (d, J = 10.1 Hz, 1 H), 5.47 (s, 66.35,66.85,72.29,79.53,83.44,95.35,110.53,110.94,118.19,118.41, 1 H),5.85 (dd, J = 10.1, 3.7 Hz,1 H), 6.12 (8, 1H), 6.62 (8, 1H), 120.64,120.99,122.75,123.24,124.17,127.94,130.44,133.50,134.17; 7.09-7.15 (m, 3 H), 7.52 (d, J = 7.1 Hz, 1H), 8.03 (br s, 1H), 9.91 mass spectrum, m/z (re1 intensity) 825 (M++ 15,5), 824 (7), 810 (br s, 1H); mass spectrum, m / z (re1 intensity) 883 (M + 1,30), (M+, 4), 792 (6), 767 (51, 766 (9), 752 (6), 751 (9), 750 (ll),749 882 (M+,71), 867 (I), 854 (ll),853 (31), 852 (581, 825 (lo), 823 (5), 748 (5), 734 (6), 674 (51,662 (5), 648 (51,632 (51,613 (71,612 (30), 724 (19), 668 (5), 643 (7), 549 (a), 496 (91, 495 (40), 469 (17), (14), 611 (6), 610 (12), 607 (51,605 (5), 591 (7), 590 (5), 536 (5), 426 (18))381 (lo), 380 (12), 355 (a), 282 (29), 273 (5), 228 (ll), 534 (6), 507 (5), 495 (61,494 (lo), 493 (7), 492 (ll),490 (5), 483 227 (la), 226 (lOO), 212 (33), 205 (16), 185 (a), 172 (111,149 (22), (6), 482 (6), 481 (5),480 (5))470 (5), 469 (9), 466 (5), 465 (5), 464 144 (17), 136 (21), 135 (43), 129 (17), 122 (271,121 (25), 111(16), (6), 393 (5), 369 (5), 367 (5), 357 (5))356 (5), 355 (9), 354 (5), 353 109 (12), 108 (ll), 107 (20), 103 (13),99 (14),97 (25))95 (20), 93 (6). 352 (6), 351 (81,344 (5), 343 (9), 341 (6), 329 (6), 327 (51,325 (17), 91 (19). (5), 313 (5), 311 (lo), 297 (6), 295 (a), 294 (131, 284 (9), 283 (6), The silyl ether of vinblastine (0.020 g) was dissolved in 5 mL 282 (17), 268 (51, 240 (7), 226 (6), 222 (6), 214 (a), 212 (5), 202 of tetrahydrofuran, and 68 WLof tetrabutylammonium fluoride (lo),201 (61, 200 (12), 198 (61, 197 (5), 196 (61, 194 (9), 188 (13), (1 M in THF, 3 equiv) was added. After 30 min, TLC showed 184 (6), 183 (61, 182 (71, 180 (7), 174 (ll),172 (6), 171 (7), 170 no remaining starting material and only the presence of vinblastine (9), 169 (a), 168 (9)r 167 (7), 160 (5), 157 (a), 156 (lo), 155 (13), in its natural conformation. Flash chromatography on silica gel 154 (loo), 144 (14), 143 (7), 141 (21), 140 (7), 138 (111, 137 (5),
Enantioselective Syntheses of Binary Alkaloids
J. Org. Chem., Vol. 56,No.2,1991 523
brought to 0 OC and trimethylsilyl trifluoromethanesulfonate (83 pL, 2 equiv) was added by syringe. After 30 min, the reaction (3aR,4R)- and (3aS,4S)-Methyl3-Benzyl-2,3,3a,4,5,7- mixture was washed with aqueous saturated sodium bicarbonate (15mL),dried (&SO$, and concentrated under reduced pressure. hexahydro-4-[(2R )-2-ethyl-2,3-dihydroxypropyl]-1RFlash chromatography on silica gel, eluting with 1:l ether-hexane, pyrrolo[2,3-d]carbazole-6-carboxylate(20b and 21b). To a gave 0.21 g (72%) of the title compound TLC Rf0.39(silica gel, stirred solution of the Nb-benzylatedindoloazepine (15a,1 g, 2.99 1:l hexane-ether, CAS blue); UV (ethanol) & 327,297,223,199 mmol) in toluene (20mL) at 70 OC was added (4R)-4-ethyl-4,5nm; IR (KBr),,Y 3375,3060,3033,2955,2859,2792,1679,1611, dihydroxypentanal acetonide (8b,0.67 g, 1.2 equiv) in toluene (5 1496,1480,1468,1439,1364,1346,1304,1294,1281,1249,1203, mL), over 15 min. After addition was complete, the reaction 1190,1177,1135,1100,1078,1054,1018,982,838,812,747,698, mixture was heated at reflux for 12 h, at which time none of the 666 cm-'; 270-MHz'H NMR (CDC13)6 0.04 (8, 9 H),0.55 (t, J starting azepine was present, as seen by TLC. The solvent was = 7.3 Hz,3 H),0.68 (dd, J = 14.6,4.7Hz,1 H),1.04 (dd, J = 14.6, removed under reduced pressure, and to the residue were added 4.7 Hz,1 H), 1.44-1.59 (m, 3 H), 1.85-1.95 (m, 1 H), 2.05 (br s, methanol (20mL) and 10% aqueous hydrochloric acid (10mL). 1 H), 2.13 (8, 3 H),2.44-2.52 (m, 3 H),2.74-2.77 (m, 1 H),2.98 Thii was heated at reflux for 20 min., the methanol was removed (8, 1 H),3.48-3.65 (m, 3 H), 3.68 (8, 3 H), 4.07 (d, J = 13.4 Hz, under reduced pressure, and the residue was made basic with 10% 1 H), 6.72-6.82 (m, 2 H),6.99 (d, J = 7.2 Hz,1 H), 7.07 (t,J = aqueous ammonium hydroxide. Extraction with diethyl ether 7.6 Hz,1 H), 7.16-7.31 (m, 7 H),7.62 (d, J = 8.2 Hz,2 H),8.87 (3X 5 mL), drying (MgS04),and concentration gave a white foam. (br s, 1 H);67.9-MHz13CNMR (CDC13)6 2.38,8.03,21.27,24.80, Flash chromatography on silica gel, eluting with ether, gave 0.53 29.61,33.74,37.52,43.00,50.66,55.10,58.38,73.50,74.26,77.75, g (38%) of the less polar 3aR,4R title isomer 18b,TLC R, 0.32 91.40,109.18,120.55,122.09,126.15,126.90,127.68,127.88,128.25, (silica gel, ether, CAS blue). This was followed by 0.56 g (40%) 128.56,129.35,129.70,137.75,139.62, 143.05,144.66,165.91,169.10; of the more polar 3aS,4Stitle isomer 19b,TLC Rf 0.25 (silica gel, mass spectrum, m / z (re1 intensity) 688 (M+,l),532 (7),503 (7), ether, CAS blue fade to purple). 476 (8),474 (30),420 (12),374 (241,373 (loo),333 (81,332 (8), For 3aR,4R,2'R isomer 18b: UV (ethanol) ,A, 327,298,201, 194 nm; IR (KBr),,Y 3390,3056,3030,2940,2856,2790,1684, 315 (9),302 (9),261 (9),230 (9),229 (29),228 (18),227 (27),214 (7),213 (12),212 (86),180 (8),168 (7),155 (60),149 (ll),147 (8), 1609,1480,1468,1439,1380,1343,1300,1280,1248,1204,1129, 129 (16),107 (8),106 (lo), 105 (14),92 (lo), 91 (81),89 (9),78 1102,1074,1048,741,697cm-l; 250-MHz 'HNMR (CDC13)6 0.78 (16),76 (15),73 (201,65 (19),56 (10). (t, J = 7.4 Hz,3 H),0.87 (dd, J = 14.7,6.8 Hz,1 H),0.91-0.98 (3aS,4S)-Methyl 3-Benzyl-2,3,3a,4,5,7-hexahydro-4(m, 1 H),1.12 (dd, J = 14.7,5.8 Hz,1 H),1.43-1.50 (m, 2 H),1.65 [(2R )-2-ethyl-24(trimethylsily1)oxyl-3-[( p-tolylsulfonyl)(dd, J = 11.8,4.5 Hz,1 H), 1.95-2.09 (m, 4 H),2.61-2.65 (m, 3 H), 2.98-2.93 (m, 1 H),3.12 (s, 1 H),3.30 (s, 2 H), 3.77 (s,3H), oxy]propyl]-lH-pyrrolo[2,3-d]carbazole-6-carboxylate(22b). By the same procedure, starting with the 3aS,dS,2'R diol 21b (0.15 4.21 t,d, J = 13.5 Hz,1 H),6.79-6.86 (m,2 H),7.00 (d, J = 7.3 g, 0.32 mmol), 0.156 g (70%) of the title compound was obtained Hz, 1 H),7.13 (t, J = 7.4Hz, 1 H),7.25-7.43 (m, 5 H),8.88 (br 8, 1 H);67.9-MHz13C NMR (CDCl3) 6 8.03,24.59,28.67,34.18, TLC Rf 0.37 (silica gel, 1:l ether-hexane, CAS blue); UV (ethanol) ,A 327,297,222,199nm; IR (KBr),,Y 3380,3059,3031,2952, 36.36,42.71,50.79,50.92,55.24,58.32,67.73,74.38,75.29,91.21, 109.21,120.61,122.16,126.98,127.77,128.28,128.78, 137.88,139.43, 2855,2792,1678,1610,1496,1480,1468,1437,1363,1345,1304, 1292,1280,1249,1202,1189,1177,1150,1134,1098,1078,1053, 142.96,165.61;mass spectrum, m / t (re1 intensity) 462 (M+,33), 1018,980,839,813,738,698,665 cm"; 270-MHz'HNMR (CDCld 431 (24),374 (18),373 (75),332 (111,329 (38),320 (14),249 (12), 6 -0.03 (s,9H),0.56 (t, J = 7.4 Hz,3 H),0.84 (dd, J = 14.6,5.0 248 (69),238 (14),234 (14),228 (27),215 (16),194 (ll),180 (14), Hz,1 H), 1.04 (dd, J = 14.6,4.6 Hz,1 H), 1.34-1.63 (m, 3 H), 169 (12),168 (20),167 (15),154 (12),141 (13),92 (9),91 (loo), 1.89-2.03 (m, 1 H),2.06 (br s, 1 H),2.34-2.35 (m, 3 H),2.45-2.55 57 (14);high resolution mass spectrum (EI, maw resolution 5OOO), (m, 3 H),2.78-2.84 (m, 1 H),3.06 (8, 1 H),3.55 (d, J = 13.4 Hz, M calcd 462.2518392,found 462.25232. 1 H),3.73 (s,3H),3.70-3.80 (m, 2 H),4.11 (d, J = 13.4 Hz,1 H), For 3aS,4S,2'R isomer 19b: UV (ethanol) ,A, 328,298,200, 193 nm; IR (KBr),,Y 3385,3029,3015,2940,2858,2791,1674, 6.774.84 (m, 2 H),7.02-7.15 (m, 2 H),7.20-7.35 (m, 7 H),7.64-7.73 (m, 2 H), 8.96 (br a, 1 H);67.9-MHz'% NMR (CDClJ 8 2.39,8.04, 1610,1496,1480,1468,1439,1380,1344,1304,1280,1249,1204, 21.27,21.43,24.73,29.71,33.76,37.61,43.02,50.74,55.05,58.37, 1130,1104,1075,1049,742,699 cm-'; 270-MHz'HNMR (CDC13) 73.63,74.22,77.67,91.32, 109.16,120.53,122.04,126.11,126.89, 6 0.75 (t,J = 7.5 Hz, 3 H),0.87 (dd, J = 14.6,4.6Hz,1 H),1.11-1.20 127.72,127.85,128.22,128.56,129.31,129.68,137.72,139.54,142.99, (m, 1 H), 1.43-1.52 (m, 2), 1.65 (dd, J = 11.7, 4.5 Hz,1 H), 144.65,165.91,169.00;mass spectrum,m/z (re1intensity) 688 (M+, 1.95-2.15 (m, 4 H), 2.56-2.66 (m, 3 H), 2.87-2.92 (m, 1 H), 3.05 7),475 (7),474 (26),374 (21),373 (1001,332(9),302 (13),229 (16), (s, 1 H), 3.31-3.33 (m, 2 H),3.71 (d, J = 13.5 Hz,1 H),3.77 (e, 228 (20),180 (6),168 (8),167 (6),155 (lo), 149 (12),106 (9),92 3 H),4.20 (d, J = 13.5 Hz,1 HI,6.79-6.86(m, 2 HI,7.00 (d, J (8),91 (66),89 (33),77 (7),75 (lo),73 (18),65 (lo),57 (8),56(8). = 7.1 Hz,1 H),7.13 (t, J = 7.7 Hz,1 H),7.24-7.43 (m, 5 H),8.88 (br s, 1 H);67.9-MHz'9c NMR (CDC13)6 7.95,24.38,28.81,34.09, (7S,5R )-Methyl 3-Benzyl-l,2,3,4,5,6,7,8-octahydro-5[(2R )-2-ethyl-2,3-epoxypropyl1-7-( 15-vindoliny1)azonino36.42,42.71,60.69,50.94,55.19,58.27,67.45,74.04,75.17,91.15, 126.98,127.74,128.25,128.75,137.82,139.31, [5,4-b]indole-7-carboxylate(31b). A solution of 0.09 g (0.13 109.20,120.56,122.10, 142.96,165.54,169.05;mass spectrum, m / z (re1 intensity) 463 ( M mmol) of (3&,4R)-methyl 3-benzyl-2,3,3a,4,5,7-hexahydro-4+ 1,23),462 (43),431 (20),374 (13),373 (601,330(9),329 (43), [(2R)-2-ethyl-2-[(trimethylsilyl)oxy]-3-[(p-tolylsulfonyl)oxy]propyl]-lH-pyrrole[ 2,3-d]carbazole-6-carboxylate(7b)and 20 p L 320 (43),249 (ll),248 (64),241 (91,238(12),234 (13),228 (24), (1.1equiv) of triethylamine in 5 mL of dichloromethanewas stirred 215 (14),194 (lo),180 (ll),169 (lo),168 (17),167 (12),154 (lo), under nitrogen and brought to 0 OC. Dropwise addition of 17 pL 141 (14),120 (12),92 (9),91 (loo),57 (13);high resolution mass (1.1equiv) of tert-butyl hypochlorite in 2 mL dichloromethane spectrum (EI, mass resolution 50001,M calcd 462.2518392,found 462.25256. and stirring for 5 min gave a solution, which by TLC was free (3aR,4R)-Methyl 3-Benzyl-2,3,3a,4,5,7-hexahydro-4- of starting compound (CAS blue) and which contained a new leas polar product (CAS purple). The reaction mixture was washed [(2R)-2-ethyl-2-[ (trimethylsily1)oxyl-3-[( p-tolylsulfonyl)with water (10mL), dried (MgSO,), and concentrated to give a oxy]propyl]-l~-pyrrolo[2,3-d]carbazole-6-carboxylate (7b). white foam, which was used in the next reaction. A solution of 0.20 g (0.43 mmol) of (3aR,4R)-methyl 3-benzyl2,3,3a,4,5,7-hexahydro-4-[ (2R)-2-ethyl-2,3-dihydroxypropyl]-lHTo a solution of the chlorination product 23b and vindoline pyrrolo[2,3-d]carbazole-6-carboxylate(20b)and triethylamine (3)(0.057 g, 0.95 equiv) in 5 mL of dry acetone was added 42 pL (0.12mL, 2 equiv) in dichloromethane (20mL) was stirred under (2equiv) of tetrafluoroboric acid-diethyl ether complex. After nitrogen and brought to 0 O C . p-Toluenesulfonicanhydride (280 5 min, 0.051g (2equiv) of silver tetrafluoroboratewas added. The reaction mixture was stirred for 10 min and then quenched with mg,2 equiv) in dichloromethane (10mL) was added dropwise over 30 min. After being stirred for an additional 24 h, the reaction the addition of 10 mL of 10% aqueous ammonium hydroxide. Extraction with dichloromethane (3X 20 mL), drying (MgSO,), mixture was washed with 10% aqueous ammonium hydroxide (3 X 15 mL), dried (MgS04),and conrentrated under reduced and concentration under reduced pressure gave a white foam, which was used in the next reaction. pressure to give a white solid. This material was dissolved in tetrahydrofuran (20mL) and The coupled imine product 25b was dissolved in 10 mL of glacial acetic acid, and 0.071 g of potassium borohydride was slowly triethylamine (0.120mL, 2 equiv) was added. The solution was eluting with 5% methanol in dichloromethane gave 0.016 g (87%) of vinblastine.
Kuehne et al.
524 J. Org. Chem., Vol. 56,No. 2, 1991
at which time TLC showed no remaining starting material and a new more polar product. The reaction mixture was cooled and flushed*withnitrogen, and 20 mg of 10% palladium on carbon was added. This was stirred under a hydrogen atmaphere at room temperature for 3 h, filtered, and concentrated. Flash chromatography on silica gel, eluting with 1% triethylamine in methanol, gave 0.28 g (90%) of the 17'-equatorial conformational isomer 34 of vincovaline: TLC R, 0.32 (silica gel, 1% methanol in di292, 284,262, chloromethane, CAS purple): UV (ethanol) A, 223,195 nm; IR (KBr),Y 3403,2956,2924,2877,1739,17219, 1658,1617,1595,1500,1461,1431,1272,1331,1304,1247,1186, 1150,1131,1099,1085,1039,1012,741cm-'; 270-MHz 'H NMR (CDC13)6 0.50-0.56 (m, 3 H), 0.91-0.99 (m, 3 H),1.15-1.58 (m, 3 H), 1.69-1.92 (m, 3 H), 2.10 (8, 3 H), 2.21-2.69 (m, 6 H), 2.70 (s,3 H), 2.71-3.11 (m, 3 H),3.41-3.58 (m, 2 H), 3.60 (s,3 H), 3.81 (s, 3 H), 5.25 (d, J = 8.1, 1H), 5.45 (8, 1H),5.82-5.91 (m, 1 H), 5.97 (8, 1H), 6.87 (8, 1H), 7.00-7.41 (m, 4 H), 9.35 (8, 1H), 10.80 (br s, 1H); mass spectrum, m/z (re1 intensity) 811 (M + 1,69), 779 (5), 752 (l), 651 (l),469 (3), 391 (261,283 (16), 281 (17), 279 (lo), 239 (40), 237 (90),234 (53), 222 (14), 221 (lo), 201 (ll), 185 (12), 179 (42), 163 (loo), 157 (30), 145 (lo), 143 (15), 129 (12), 121 (14), 113 (19);CD (0.024mg/mL methanol) X (ellipticity)214 (12), 225 (-114), 258 (-ll),0.240 mg/mL) 307 (28). This product was then dissolved in toluene and heated at reflux for 8 h. Concentration and flash chromatography on silica gel, eluting with 9:l dichloromethane-methanol, gave 0.27 g (95%) 60.18,63.44,65.71,79.69,83.68,94.24,110.30,115.05,118.19,118.95, of vincovaline (14b): TLC R, 0.42 (silica gel, 5% methanol in 122.01,123.44,124.37,125.52,126.36,127.80,127.96,130.04,132.23, dichloromethane, CAS maroon); UV (ethanol) X, 205,216 shld, 135.04, 140.10,152.93,158.12,170.70,174.60; high resolution mass 247,284,292,301nm; IR (KBr) Y- 3458,3424,3025,2962,2931, spectrum (EI, mass resolution 12000),M calcd 900.4672941, found 2879,2852,2813,1740,1676,1614,1500,1460,1433,1371,1334, 900.46303; mass spectrum, m/z (re1 intensity) 901 (ll),900 (M', 1296,1249,1226,1191,1174,1146,1106,1095,1034,963,927,903, 33), 898 (6),841 (6), 839 (71,838 (131,825 (291,824 (521,810 (101, 804, 741 cm-'; 270-MHz 'H NMR (CDC13)S 0.38 (t, J = 7.1 Hz, 809 (9), 793 (71,792 (91, 788 (7), 766 (61,751 (71,741(71,665 (61, 3 H), 0.89 (t, J = 7.0 Hz, 3 H), 0.98-1.80 (m, 6 H), 2.07 (8, 3 H), 649 (8),541 (6), 540 (12), 527 (lo), 470 (ll),469 (211,450 (6), 444 2.10-2.51 (m, 4 H), 2.73 (9, 3 H), 2.17-2.82 (m, 2 H), 3.11-3.54 (9), 431 (14), 381 (7), 380 (lo), 379 (8), 373 (6), 370 (6), 369 ( l l ) , (m, 4 H), 3.56 (s,3 H), 3.79 (8, 6 H), 3.98-4.11 (m, 1 H), 5.23 (d, 356 (lo), 355 (35), 325 (6), 310 (7), 297 (6), 295 (6), 283 (7), 282 J = 8.7 Hz, 1 H), 5.45 (9, 1 H), 5.79 (dd, J = 10.0,4.7 Hz,1 H), (29), 273 (18),261 (17), 258 (7), 244 (6),240 (6), 231 (6), 230 (31), 6.14 ( 8 , 1 H), 6.72 (8, 1 H), 7.05-7.21 (m, 3 H), 7.52 (d, J = 7.4 222 (9), 218 (7), 217 (8),214 (8),202 (lo), 200 (9), 190 (6). 188 Hz, 1H), 8.11 (8, 1 H), 9.68 (br s, 1 H); mass spectrum, m/z (re1 (13), 185 (6), 182 (6), 174 (7), 171 (6), 170 (61,168 (81,158 (6), 155 intensity) CI 811 (M 1, 14), 793 (5), 753 (3), 431 (4), 419 (3), (S),154 (62), 144 (13), 143 (7), 141 (15), 140 (7), 136 (24), 135 (67), 393 (4), 392 (221, 391 (loo), 389 (121, 375 (31, 307 (61, 279 (18), 134 (25), 130 (8),124 (9), 123 (7), 122 (36), 121 (311, 120 (8),108 261 (9), 186 (5), 185 (3), 184 (4), 177 (3), 167 (4), 149 (14), 113 (131, 107 (301, 106 (9),93 (17),92 (25), 91 (100), 84 (7),82 (6),81 (7); high resolution mass spectrum (EI, mass resolution 12000), (7), 79 (7), 77 (8), 70 (6), 65 (14), 60 (7), 58 (30), 57 (9). (7R,5S)-Methyl 3-Benzyl-1,2,3,4,5,6,7,8-octahydro-5- M calcd 810.4203801, found 810.41685; mass spectrum, m / t (re1 intensity) 838 (7), 826 (7), 825 (17), 824 (32), 811 (9), 810 (17), [(2R )-2-ethyl-2,3-epoxypropyl1-7-( 15-vindoliny1)azonino808 (7), 779 (9), 766 (6), 753 (7), 752 (15), 751 (13), 651 (7), 649 [5,4-b]indole-7-carboxylate(33b). By the same procedure, (7), 469 (12), 356 (9), 355 (35), 283 (7), 282 (21), 222 (7), 214 (6), starting with 0.085 g (0.12 mmol) of the 3aS,4S,2'R isomer 22b 202 (6), 200 (7), 174 (6), 168 (8),156 (61,155 (12), 154 (loo), 144 of the silyl tosylate, 0.077 g (69%) of the title compound was (9), 141 (15), 140 (ll),136 (21), 135 (56), 130 (6), 124 (32), 123 obtained: TLC R,0.41 (silica gel, ethyl acetate, CAS brown); UV (6), 122 (28), 121 (25), 108 (lo), 107 (22), 106 (7), 93 (12), 92 (9), 290,258,212, 194 nm; IR (KBr) vmm 3460,3030, (ethanol) X, 2935,2800,1743,1622,1500,1460,1441,1369,1240,1235,1170, 91 (161, 84 (81, 83 (91, 82 (7), 70 (81, 60 (7),58 (34), 57 (9); CD (0.019 mg/mL methanol) X (ellipticity)214 (loo),225 (-167), (0.190 1040,736,695 cm-'; 270-MHz 'H NMR (CDClJ 6 0.46 (t,3 H), mg/mL) 258 (32), 307 (-32). 0.73 (t, 3 H), 1.10-1.36 (m, 10 H), 1.58-1.71 (m, 2 H), 2.07 (8, 3 Leurosidine (13) and Its 17'-Equatorial Conformational H), 2.19-2.67 (m, 10 H), 2.79 (s,3 H), 2.87-3.10 (m, 1H), 3.35-3.52 Isomer 35b. By the same procedure, starting with 0.10 g (0.11 (m, 3 H), 3.57 ( 8 , 3 H), 3.63-3.73 (m, 2 H), 3.82 (8, 6 H), 5.28 (d, mmol) of the D-seco epoxide dimer 31b and adding 1.5 equiv of 1 H), 5.45 (9, 1 H), 5.85 (dd, 1 H), 6.14 (8, 1HI, 6.9-7.45 (m, 9 glacial acetic acid, 0.054 g (60%) of the 17'-equatorial conforH), 8.09 (br s, 1H), 9.76 (br s, 1H); 67.9-MHz '% NMR (CDC13) mational isomer 35b was obtained: TLC R 0.19 (silica gel, 1% S 8.10, 8.68,20.92, 26.26,26.64, 29.21, 29.54, 30.60, 34.03, 38.53, triethylamine in dichloromethane,CAS purpd); W (ethanol) X, 42.69,45.15,50.26,50.34,52.03,52.14,53.49,53.85,54.14,54.44, 291,285,262,222,195 nm; IR (KBr),Y 3457,3407,2957,2930, 57.83, 58.77,65.05,65.93,75.98,76.20,77.45,79.71,83.57,93.70, 2877,2852,1740,1616,1595,1498,1458,1432,1371,1332,1301, 110.16,118.11,118.79,121.92,123.13,123.99,126.61,128.00,128.08, 1250, 1191, 1172, 1147, 1132, 1110, 1085, 1042, 743, cm-'; mass 128.16,130.12,134.86,140.19,153.05,158.37,170.39,171.54;high spectrum, m / t (re1 intensity) 810 (M+, 31, 779 (2), 651 (2), 469 resolution mass spectrum (EI,mass resolution 120001, M calcd (l),308 (2), 297 (5), 282 (5), 187 (3), 182 (11,154 (7), 149 (5), 141 900.4672941, found 900.46083; mass spectrum, m/z (re1intensity) (2), 140 (8), 123 (3), 122 (5), 121 (3), 112 (4), 109 (4), 107 (6); CD 901 (12), 900 (M', 26), 842 (61,838 (8),825 (lo), 824 (18), 810 (8), (0.026 mg/mL methanol) X (ellipticity)214 (-185), 225 (167), 258 792 (71, 751 (6), 649 (6), 540 ( l l ) , 527 (8),470 (7), 469 (17), 444 (41), (0.260 mg/mL) 307 (-9). (7), 431 (9), 381 (6), 380 (€9,379 (7), 369 (9), 356 (6), 355 (19), 311 After heating 0.04 g of the above compound at reflux in toluene (6), 295 (6), 283 (6), 282 (21), 272 (8),261 (16), 260 (6), 258 (6), for 72 h, 0.032 g (80%)of leurosidine (13) was obtained TLC 231 (6), 230 (29), 222 (81, 218 (6), 217 (81, 214 (8), 202 (9), 188 (lo), 170 (6), 168 (7), 158 (6), 155 (6), 154 (40), 144 (ll),143 (8), R 0.24 (silica gel, 5% methanol in dichloromethane, CAS brown); d V (ethanol) A, 141 (ll),140 (€9,136 (23), 135 (60), 134 (221,130 (9), 124 (9), 122 300,290,260,220,195nm; IR (KBr) u,, 3467, (27), 121 (26), 120 (8),108 (111,107 (261,106 (11),93 (13),92 (24), 2957,2936,2879,2848,2815,1740,1616,1503,1459,1432,1371, 1331,1244,1229,1039,738 cm-'; 270-MHz 'H NMR (CDC13) 6 91 (100),81 (6), 79 (7), 77 (9), 65 (18),63 (6), 60 (7), 58 (30), 55 0.82 (t, J = 7.6 Hz,3 H), 0.95 (t, J = 7.6 Hz,3 H),1.16-1.41 (m, (e), 51 (6). 2 H), 1.52-1.59 (m, 1H), 1.73-1.84 (m, 3 H),2.11 (s,3 H), 2.11-2.28 Vincovaline (14b) and Its 17'-Equatorial Conformational Isomer 34. A solution of the D-SeCO epoxide dimer 33b (0.35 g, (m, 6 H), 2.40-2.50 (m, 1 H), 2.67-2.87 (m, 3 H), 2.72 (8, 3 H), 0.39 mmol) in 10 mL of methanol was heated at reflux for 48 h 2.92-3.00 (m, 1 H), 3.11-3.21 (m, 2 H),3.25-3.43 (m, 4 H), 3.61
added. After being stirred for 10 min, the reaction mixture was poured onto ice and made strongly basic with concentrated ammonium hydroxide. Extraction with dichloromethane (3 X 20 mL), drying (MgSO,), and concentration under vacuum gave a white foam: TLC R, 0.56 (silica, ethyl acetate, CAS brown). This material (27b) was dissolved in 20 mL of tetrahydrofuran, and 0.375 mL (3 equiv, 1 M in THF)of tetrabutylammonium fluoride was added. After 30 min, TLC showed no remaining starting compound and the preeence of a new, more polar product. The solution was washed with aqueous saturated sodium bicarbonate, dried (MgSO,), and concentrated under vacuum. Flash chromatographyon silica gel, eluting with ethyl acetate, gave O.Os0 g (71%)of the title compound TLC R, 0.43 (silica, ethyl acetate, CAS brown); UV (ethanol) A, 288,258,212,195 nm; IR (film) ,Y 3460,3025,2965,2935,2792,1743,1612,1501,1460, 1432, 1369,1336,1300,1242,1225,1172,1143,1124,1105,1041,960, 815, 738, 697 cm-'; 270-MHz 'H NMR (CDClJ S 0.50 (t, 3 H), 0.84 (t, 3 H), 0.91-0.99 (m, 1 HI, 1.28-1.84 (m, 8 HI, 1.92-2.29 (m, 2 H), 2.11 (s,3 H), 2.40-2.69 (m, 8 H), 2.68 (a, 3 H), 2.91-3.35 (m, 4 H), 3.51 ( 8 , 3 H),3.02-3.75 (m, 5 H), 3.78 ( 8 , 3 H), 3.82 (9, 3 H), 5.31 (d, 1 H), 5.48 (8, 1 HI, 5.84 (dd, 1 HI, 6.14 (8, 1 HI, 6.81-6.92 (m, 3 H), 6.99-7.07 (m, 3 H), 7.11-7.20 (m, 2 H),7.39-7.42 (m, 1 H), 8.01 (br s, 1 H), 9.97 (br s, 1 H); 67.9-MHz 13C NMR (CDClS)6 8.43,8.82, 20.95,25.50,25.89, 29.29,30.89, 33.53, 38.53, 40.33, 42.80,44.73, 50.07, 51.95, 52.12, 53.27,55.66, 56.25, 58.77,
+
Enantioselective Syntheses of Binary Alkaloids
J. Org. Chem., Vol. 56, No. 2, 1991 525
followed by warming to 0 "C over 1h. Thallium dimethyl mawas added and the mixture waa stirred lonate (1.14 g, 3.41 "01) at room temperature for 3 h and then at reflux for 20 h. The cooled reaction mixture was filtered and concentrated. Flash chromatography on silica gel, eluting with 3 2 ethel-hexane, gave 0.77 g of the title compound (78%) crystallized from methanol: TLC R 0.50 (silica gel, 3:2 ether-hexane, CAS gray-green); UV (ETOd) A- 196,224,284,292,328nm;IR (film) v,, 3412,3060, 3030,2958,2900,2839,1740,1670,1618,1580,1493,1460,1435, 1392,1373,1337,1283,1245,1175,1155,1144,1075,1050,1032, 960,928,870,796,742,700 cm-'; 'H NMR (CDCl,) 6 1.42 (d, J = 6.7 Hz, 3 H), 2.74-2.89 (m, 4 H), 3.62 (d, J = 13.4 Hz, 1H), 3.73-3.82 (m, 7 H), 4.00-4.08 (m, 1HI, 7.03-7.46 (m, 9 HI, 8.39 (br s, 1H); 67.9-MHz '% NMR (CDClJ 6 14.86,25.38,52.88,52.96, 59.51,62.81,64.82, 110.81, 114.90, 118.42, 119.31, 122.18, 126.71, 127.54, 128.08, 128.72, 129.48, 135.14, 143.49, 169.71; maw spectrum, m/z (re1 intensity) 407 (M 1, 25), 406 (73), 391 (6), 301 (43), 275 (13), 273 (37), 272 (36), 270 (17), 269 (14), 264 (15), 260 (19), 242 (lo), 241 (9), 228 (28), 227 (9), 214 (la), 209 (13), 181 (7), 169 (lo), 159 (a), 155 (7), 154 (29), 140 (7), 128 (9), 127 (la), 106 (9), 105 (loo), 103 (ll),91 (lo), 79 (20), 77 (20), 59 (14). Methyl 3-[(S)-a-Methylbenzyll- 1,2,3,4,5&6-hexahydroazepino[4,5-b]indole-5-carboxylate (41). A solution of the diester azepine 52 (0.75 g, 1.85 mmol), lithium chloride (0.78 g, 1equiv), and triethylamine hydrochloride (0.127 g, 0.5 equiv) in dimethylacetamide (20 mL) was heated at 120 "C for 1h, at which time TLC (2% methanol in dichloromethane) showed no remaining starting material and the presence of a new, more polar compound. Brine (20 mL) was added to the reaction mixture and 2800,2755,1720,1650,1600,1583,1495,1474,1453,1410,1387,the resulting solution was extracted with ether (3 X 25 mL). The 1375,1340,1320,1310,1285,1219,1155,1130,1110,1080,1050, combined ether layers were dried over magnesium sulfate. Concentration and flash chromatographyon silica gel, eluting with 1028,1010,1000,970,949,930,912,800,767,734,700,624,615, 3:2 ether-hexane, gave 0.51 g (80%) of the title compounds as 604 cm-'; 270-MHz 'H NMR (CDCl,) 6 1.42 (d, J = 6.8 Hz, 3 H), two diastereomers: TLC R,0.41,0.45 (silicagel, 3 2 ethel-hexane, 2.41 (t, J = 5.9 Hz, 4 H), 2.66-2.81 (m, 4 H), 3.62 (4, J = 13.5, CAS blue); UV (ETOH)A- 196,203,225,283,291nm; IR (film) 6.7 Hz, 1H), 7.22-7.36 (m, 5 H); 67.9-MHz 13C NMR (CDCl,) 6 Y, 3392,3060,3030,2952,2829,1733,1600,1494,1465, 1454, 19.11,41.42,49.88,63.25, 126.98, 127.21, 128.21, 143.47, 208.93; 1435,1370,1340,1286,1245,1208,1163,1050,1025,910,850,742, mass spectrum m/z (re1 intensity) 204 (M + 1,191,203(M+,30), 717, 700 cm-'; 270-MHz 'H NMR (CDCl,) 6 1.42 (d, J = 6.7 Hz, 189 (14), 188 (98), 143 (13), 126 (51), 118 (35), 106 (14), 105 (loo), 3 H), 2:58-3.2 (m, 6 H), 3.4-3.53 (m, 1 H), 3.65-3.71 (25, 3 H), 104 (13), 103 (20), 98 (14), 91 (42), 79 (30), 78 (12), 77 (45), 56 3.96-4.08 (m, 1H), 7.02-7.16 (m, 2 H), 7.1s7.46 (m, 7 H), 8.1-8.3 (50), 55 (13), 51 (17). (%,1 H); 67.9-MH~'3C NMR (CDClJ 6 14.83,17.39,24.89; 25.32, N-[(S)-a-Methylbenzyl]tetrahydro-y-carboline(48). 46.28, 46.67, 51.96,52.09, 53.64, 54.44,56.06,63.69,64.20,110.57, Phenylhydrazine hydrochloride (2.8 g, 19.36 "01) in glacial acetic 113.84,117.92,118.96,121.21,121.25,126.66,127.49,127.93,128.02, acid (60 mL) and the N-(methylbenzyl)-4-piperidone43 (4.32 g, 128.53, 132.12, 132.26, 134.81, 143.30, 143.97, 172.38; mass spec21.30 mmol) were stirred at room temperature for 3 h. Concentrum, m/z (re1 intensity) 349 (M + 1, 29), 348 (M', 561,333 (3), trated HCl(40 mL) was then added, causing the reaction to tum 275 (8), 243 (68), 216 (14), 215 (56), 214 (78), 202 (25), 183 (lo), dark red. The mixture was heated at 65 OC for 3 h, at which time 170 (lo), 169 (15), 156 (30), 155 (lo), 154 (24), 147 (ll), 146 (13), the acetic acid was removed under reduced pressure (70 "C). The 134 (9), 128 (9), 106 (9), 105 (loo), 103 (9), 79 (12), 77 (18). residue was taken up in dichloromethane (150 mL) and basified (3aR,4R)- a n d (3aS,4S)-Methyl 3-[(S)-a-Methylwith potassium carbonate. Water was added (50mL), the organic benzyl]-2,3,3a,4,5,7- hexahydro-4-[ (2R )-2-et hyl-2,3-dilayer was separated, and the aqueous layer was extracted further hydroxypropyll-1H-pyrrolo[2,3-d]carbazole-6-carboxylate with 2 X 50 mL of dichloromethane. The combined dichloroAcetonide (54 and 55). The mixture of the above azepines 41 methane layers were dried over magnesium sulfate. Concentration in anhydrous toluene (15 mL) was stirred under (0.15 g, 0.43 "01) and flash chromatography on silica gel, eluting with 2:l ethernitrogen at 70 "C. (4R)-4-Ethyl-4,5-dihydroxypentanal acetonide hexane followed by crystallization from methanol, gave 4.25 g of (8b, 0.095 g, 1.2 eq) in toluene (2 mL) was added slowly via syringe, the title compound (71%);mp (methanolate) 80-84 "C dec. TLC and the reaction mixture was heated at reflux for 24 h. ConR,0.33 (silica gel, 3 2 ether-hexane, CAS blue-green);UV (ETOH) centration and flash chromatography on silica gel, eluting with A, 207,223,277,282 nm; IR (KBr),v 3402,3150,3058,3035, 2975,2920,2802,2745,1625,1598,1493,1475,1452,1440,1272, 1:l ether-hexane, gave 0.133 g (60%) of a mixture of the title 1330,1312,1281,1265,1238,1183,1148,1121,1102,1088,1063, compounds: TLC R, 0.54 (silica gel, 3 2 ether-hexane, CAS blue); 270-MHz lH NMR (CDCl,) integration of indole protons (8.87, 1030,1010,970,738,700,635 cm-'; 'H NMR (CDCl,) 6 1.51 (d 1H):(8.98,1 H); mass spectrum, m / z (re1 intensity) 516 (M+,4), J = 6.7 Hz, 3 H), 2.09 (br s, 1 H), 2.58-2.72 (m, 3 H), 2.85-2.92 515 (12), 501 (3),388 (13), 387 (44),303 (5), 302 (231,283 (4), 241 (m, 1 H), 3.36 ( 8 , 3 H), 3.57-3.71 (m, 2 H), 3.94 (d, J = 13.5 Hz, (31,238 (4), 228 (7), 214 (5), 198 (6), 194 (4), 187 (20), 169 (5), 168 1 H), 7.00-7.10 (m, 2 H), 7.16-7.41 (m, 7 H), 7.97 (br 8, 1 H); 67.9-MH~"C NMR (CDC13) 6 20.11, 23.97, 46.93, 47.77, 50.57, (a), 167 (a), 159 (8), 155 (6), 154 (7), 140 (9), 132 (a), 129 (17), 127 64.09, 108.93, 110.56,117.15,119.15,121.00,126.39,126.90,127.56, (41), 115 (18), 113 (9), 111 (5), 109 (61, 106 (lo), 105 (loo), 81 (13), 128.28,132.40, 136.19,144.54;mass spectrum, m / z (re1 intensity) 72 (53), 71 (15), 59 (52). 277 (M + 1, ll),276 (M+, 41), 275 (9), 261 (3), 171 (14), 144 (20), (3aR,4R )- and (3aS,4R )-Methyl 3 4 (S)-a-Methyl143 (loo), 118 (4), 115 (7), 105 (25), 103 (7), 91 (lo), 79 (a), 77 benzyl]-2,3,3a,4,5,7-hexahydro-4-[(2R )-2-ethyl-2,3-dihydroxypropyll- la-pyrrolo[ 2,3-d]carbazole-6-carboxylate (W, 56 (5), 51 (5). (56 and 57). The mixture of the acetonides 54 and 55 (0.133 g, Dimethyl 3 4 (S)-a-Methylbenzyll- 1,2,3,4,5,6- hexahydro0.26 mmol) in methanol (20 mL) and 10% aqeuous hydrochloric ampino[ 4,5-b]indole-5,5-dicarboxylate(52). To a solution of acid (5 mL) was stirred at reflux for 30 min. Methanol was N-[ (S)-c~-methylbenzyl]tetrahydro-y-carboline (methanolate) (48, removed under reduced pressure, and the reaction mixture was 0.75 g, 2.43 mmol) and triethylamine (0.37 mL, 2.68 mmol) in basified with 10% ammonium hydroxide and extracted with ether tetrahydrofuran (20 mL), stirring at -78 "C (dry ice, acetone) (3 X 25 mL). The combined ether layers were dried over magunder nitrogen, was added tert-butyl hypochlorite (0.313 mL, 2.68 nesium sulfate. Concentration and flash chromatography on silica mmol). The reaction mixture was stirred at -78 "C for 15 min
(s,3 H), 3.74 (8, 1H), 3.80 (s,6 H), 5.31 (d, J = 8.9 Hz, 1H), 5.47 (8, 1 H), 5.87 (m, 1 HI, 6.12 (s, 1 HI, 6.56 (8, 1 H), 7.11-7.19 (m, 3 H), 7.53 (d, J = 6.8 Hz, 1 H), 7.98 (8, 1 H), 9.79 (s, 1H); high resolution mass spectrum (EI, mass resolution 12 0001, M calcd 810.4203801, found 810.41718; mass spectrum, m/z (re1intensity) 838 (ll), 825 (15), 824 (32), 811 (6), 810 (17), 780 (6), 779 (lo), 766 (a), 753 (7), 752 (14), 751 (81,651 (7). 649 (6), 469 ( l l ) , 369 (9), 356 (9) 355 (34), 295 (7), 283 (61,282 (21), 272 (6), 222 (7), 214 (7), 202 (6), 200 (7), 188 (9), 174 (6), 170 (6), 168 (6), 155 (ll), 154 (loo), 144 (lo), 141 (15), 140 (lo), 136 (211,135 (52), 130 (6), 124 (32), 123 (6), 122 (30), 121 (25), 108 (ll), 107 (21), 106 (7), 93 (12),92 (6),91 (8),84 (8),83 (10),82 (8),81 (6),70 (8),60 (61, 58 (40),57 (9), 55 (7); CD (0.027 mg/mL) X (ellipticity) 214 (-291), 225 (1331, 258 (79), (0.270 mg/mL) 307 (20). N-[(S)-a-Methylbenzyl]-4-piperidone (43). @)-(-)-aMethylbenzylamine (46, 2.0 g, 16.5 mmol), ethanol (25 mL), potassium carbonate (4.79 g, 34.6 mmol), and water (12 mL) were stirred in a two-necked flask equipped with a reflux condenser and a dropping funnel containing N,N-dimethyl-4-oxopiperidinium iodide (45,4.21 g, 16.5 "01) in water (12 mL). After achieving vigorous reflux the piperidone was added over 30 min, and the mixture was heated at reflux for another 30 min. The reaction mixture was then cooled, the ethanol was removed under reduced pressure, and the residue was extracted with 3 X 100 mL of ether. The ether layers were combined and dried over magnesium sulfate. Concentration and flash chromatography, eluting with ether, gave 2.5 g of the title compound (75%): TLC R,0.43 (silica gel, 3 2 ethel-hexane, CAS char); UV (EtOH) A- 204,321 nm; IR (neat),v 3418,3085,3062,3010,2972,2940,2908,2880,
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Kuehne et al.
526 J. Org. Chem., Vol. 56,No. 2, 1991
bazole-6-carboxylate (58) and triethylamine (17 pL, 1.1equiv) in gel, eluting with ether, gave 0.085 g of the less polar 3aR,4R,2'R dichloromethane (5 mL) was stirred under nitrogen and brought title isomer 56 (69%): TLC R, 0.44 (silica gel, 9 1 dichloroto 0 O C . tert-Butyl hypochlorite (14 pL, 1.1equiv) in dichloromethane-methanol, CAS blue). This was followed by 0.028 g methane (2 mL) was added by syringe, and the mixture was stirred (23%) of the more polar isomer 57 (3aS,4S,2'R): TLC R, 0.32 for 5 min at which time, by TLC, the mixture was free of starting (silica gel, 9 1 dichloromethane-methanol,CAS blue fade to material. The solution was washed with water (10 mL), dried over purple). Diastereomeric excess: 47%. sodium sulfate, and concentrated under vacuum to give a white For the 3aR,4R,2'R isomer 56: W (ethanol) A- 203,225,299, solid, which was used in the next reaction: R 0.59 (silica, ethyl 328 nm; IR (film) u,, 3460,3390,2972,2935,1730,1672,1610, acetate, CAS brown). To a solution of the chforination product 1480,1467,1438,1378,1300,1282,1250,1203,1133,1045,745, and vindoline (0.052 g, 1equiv) in dry acetone (5 mL) was added 700 cm-l; 2 7 0 - m ~ 'H NMR (CDC13)6 0.80-94(m, 5 H), 1.14 (dd, tetrafluoroboric acid-diethyl ether complex (43 pL, 2 equiv). After J = 14.7, 7.4 Hz, 1 H), 1.49-1.74 (m, 6 H), 1.91-2.02 (m, 1 HI, 5 min, silver tetrafluoroborate (0.044 g, 2 equiv) in dry acetone 2.15-2.27 (m, 2 H), 2.49-2.67 (m, 3 H), 2.95 (t, J = 8.3 Hz, 1 H), (1 mL) was added. The resulting heterogeneous mixture was 3.06 (bra, 1 H), 3.33-3.44 (m, 2 H), 3.77 (8, 3 H), 4.09-4.18 (m, stirred for 10 min, at which time 10% ammonium hydroxide (5 1 H), 5.95 (d, J = 7.3 Hz, 1H), 6.58 (t,J = 7.3 Hz, 1 H), 6.73 (d, mL) was added, Extraction with dichloromethane (3 X 15 mL), J = 7.7 Hz,1H), 7.03 (t,J = 7.7 Hz, 1 H), 7.29-7.45 (m, 5 H), drying over sodium sulfate, and concentration under vacuum gave NMR (CDC13)6 8.16, 21.13,24.05, 8.81 (br s, 1H); 67.9-MHz a white foam. 28.87, 34.68, 36.59,41.06,45.52,50.89,55.02, 59.11,67.70,71.38, The above material was then dissolved in glacial acetic acid 75.17, 90.50, 108.90,120.52,122.21,127.07,127.43,128.08,128.44, (10 mL) and, with stirring, potassium borohydride (0.062 g, 10 137.77, 140.65, 142.73, 165.43, 169.10. (3aR,4R)-Methyl 3-[(S)-~-Methylbenzyl]-2,3,3a,4,5,7- eq) was slowly added. After 15 min, the reaction mixture was poured onto ice and made strongly basic with concentrated amhexahydro-4-[ (2R)-%ethy1-2-hydroxy-3-[ (p-tolylsulfonyl)monium hydroxide. Extraction with dichloromethane (3 X 15 oxy]propyl]-1H-pyrrolo[2,3-d]carbazole-6-carboxylate.A mL), drying (Na2S04),and concentration under vacuum gave a solution of 80 mg (0.17 mmol) of (3aR,4R)-methyl 3-[(S)-awhite foam: TLC R 0.53 (silica gel, ethyl acetate, CAS brown). methylbenzyl]-2,3,3a,4,5,7-hexahydro-4[ (2R)-2-ethyl-2,3-diThis product was dissolved in tetrahydrofuran (10 mL) and hydroxypropyl]-lH-pyrrolo[2,3-d]carbazole-&carboxylate(56) and brought to 0 "C. Tetrabutylammonium fluoride (0.228 mL, 2 47 mL (0.34 mmol) of triethylaminein 20 mL of dichloromethane equiv, 1.0 M in THF) was added by syringe, and the reaction of p-toluenesulfonic was brought to 0 O C , and 110 mg (0.34 "01) mixture was stirred for 15 min, at which time TLC showed anhydride was added. The reaction mixture was stirred under complete conversion of starting material to a more polar product. nitrogen for 30 h and then washed with 10% ammonium hyThe solution was washed with aqueous saturated sodium bidroxide. The organic layer was dried over sodium sulfate and carbonate, dried over sodium sulfate, and concentrated under concentrated under reduced pressure to give a white solid, which vacuum. Flash chromatography on silica gel, eluting with ethyl was taken directly on to the next reaction: TLC R, 0.37 (silica acetate, gave 0.084 g (73%) of the title compound TLC R, 0.44 gel, 4:l ether-hexane, CAS blue). (silica gel, ethyl acetate, CAS brown); W A- 213,262,289 nm; (3aR,4R)-Methyl 3-[(S)-~-MethyIbenzy1]-2,3,3a,4,5,7IR (film) u,, 3470,3028,2965,2930,2875,2575,2240,1740,1610, hexahydro-4-[ (2R)-2-et hyl-24 (trimethylsily1)oxyl-3-[( p 1500,1456,1430,1367,1325,1235,1170,1140,1100,1080,1035, tolylsulfonyl)oxy]propyl]- lH-pyrro10[2,3-d]carbazole-65.90 (dd, 815,755,730,696,640cm-'; 270-MHz 'H NMR (CDClJ carboxylate (58). A solution of (3aR,4R)-methyl 3-[(S)-u6 0.55 (t, J = 7.2 Hz, 3 H), 0.88 (t, J = 7.3 Hz,3 H),1.20 (d, J methylbenzyl]-2,3,3a,4,5,7-hexahydro-4[ (2R)-2-ethyl-2hydroxy-3-[(p-tolylsulfonyl)oxy]propyl]-lH-pyrrolo[2,3-d]carba- = 6.6 Hz, 3 H), 1.22-1.46 (m, 5 H),1.66-2.04 (m, 3 H), 2.12 (a, 3 H), 2.17-2.23 (m, 2 H), 2.35-2.63 (m, 6 H), 2.69 (a, 3 H), 2.74-2.80 zole-6-carboxylate from the previous reaction and triethylamine (m, 2 H), 3.00 (d, J = 14.4 Hz,2 H),3.25-3.55 (m, 3 H), 3.59 (a, (35 pL, 1.5 equiv) in tetrahydrofuran (20 mL) was stirred under 3 H), 3.63-3.76 (m, 2 H), 3.81 (s,6 H), 5.36 (d, J = 10.2 Hz, 1H), nitrogen and brought to 0 O C . Trimethylsilyl trifluoro5.51 (a, 1 H), 5.90 (dd, J = 13.2, 6.6 Hz,1 H), 6.10 (a, 1 H), 6.9 methanesulfonate (49 pL, 1.5 equiv) was then added by syringe. (8, 1H), 7.03-7.41 (m, 9 H), 9.7 (br s, 1 H); 67.9-MHz lBC NMR The solution was stirred for 20 min, then washed with 10 mL of (CDC13) 6 8.40,8.63, 15.36, 20.98,25.69,26.04,30.89,34.38,36.06, aqueous saturated sodium bicarbonate, dried over sodium sulfate, 38.54,40.11, 42.89, 44.67, 48.99, 50.61, 50.74, 52.07, 52.12, 52.96, and concentrated under reduced pressure. Flash chromatography 53.33,55.60, 55.79, 56.62, 58.77,63.36,66.44, 76.41,76.53, 79.73, on a silica gel column, eluting with 3:2 ether-hexane, gave 86 mg 83.63,94.31, 110.31, 116.51,118.20,118.92, 121.99, 122.10,125.36, (73% from diol) of the title compound: TLC R, 0.45 (silica gel, 124.38,124.89,126.25,127.13,127.94,129.32,130.10,134.96,144.64, 3 2 ether-hexane, CAS blue); W (ethanol) A- 200,224,255,297, 153.01, 158.26, 170.77, 171.60, 174.36; maas spectrum, m/z (re1 330 nm; IR (KBr) umaX3385,3060,3030,2975,2950,2858,1738, intensity) 915 (M 1,5), 810 (5), 566 (12), 540 (7), 527 (12), 469 1677,1608,1495,1480,1465,1455,1437,1362,1303,1295,1280, 1250,1240,1200,1190,1176,1155,1130,1096,1083,1062,1050, (6), 380 (lo), 296 (5), 295 (9), 283 (5), 282 (14), 276 (ll),275 (a), 273 (6), 258 (5), 245 (5), 244 (19), 233 (13), 232 (9),222 (5), 188 1030,980,910,840,812,780,750,735,705,636,552 cm-l; 270-MHz (5), 172 (6), 171 (7), 149 (6), 148 (5), 145 (6), 144 (lo), 140 (a), 136 lH NMR (CDC13)6 0.0 (a, 9 H), 0.52 (J= 6.5 Hz, 3 H), 0.58-0.65 (a), 135 (33), 134 (5), 130 (6), 129 (7), 122 (12), 121 (13), 119 (6), (m, 1H), 0.98-1.14 (m, 2 H), 1.31-1.55 (m, 3 H), 1.44 (d, J = 6.9 115 (6), 112 (5), 111 (lo), 109 (5), 108 (5), 107 (lo), 106 (ll),105 Hz, 3 H), 1.76-1.86 (m, 1 H), 2.04-2.06 (m, 1 H), 2.30 (a, 3 H), (loo), 104 (14), 103 (lo), 100 (5), 99 (9), 97 (E),95 (5), 93 (7), 91 2.31-2.57 (m, 3 H), 2.79 (bra, 1H), 3.58-3.71 (m, 1H), 3.87-3.93 (lo), 87 (97). (m, 1 H), 5.77 (d, J = 7.3 Hz, 1H), 6.45 (t,J = 7.5 Hz, 1 H), 6.60 N-[(S)-1-( l-Naphthyl)ethyl]-4-piperidone(44). (S)-(-)(d, J = 7.7 Hz, 1 H), 6.91 (t, J = 7.5 Hz, 1 H), 7.13-7.28 (m, 7 1-(1-Naphthy1)ethylamine(47) (2 mL, 12.38 mmol), ethanol (25 H),7.63 ( d , J = 7.2 Hz, 2 H),8.78 (br s, 1H);67.9-MHz '% NMR (CDC13) 6 2.54,8.26,21.19, 21.51, 23.59, 29.23, 34.52,37.03, 41.28, mL), potassium carbonate (3.59 g, 25.97 mmol), and water (12 iodide mL) were heated at reflux. N,N-Dimethyl-4-piperidone, 45.49,50.60,54.91,59.25,72.19, 74.11,77.82,90.84, 108.87, 120.44, salt (45) (3.16 g, 12.38 mmol) in water (12 mL) was added by 122.18,127.12,127.47,127.98,128.12,128.46,129.74,133.01,137.67, dropping funnel over 30 min. The mixture was then stirred for 140.48, 142.91, 144.70, 165.42, 169.08; mass spectrum, m / r (re1 another 30 min at reflux temperature. The solution was cooled, intensity) 702 (M', 6), 517 (6),489 (9),488 (28), 388 (26),387 (loo), 384 (€0,346 (lo), 294 (a), 283 (ll),229 ( E ) , 228 (17), 227 (12), ethanol was removed under reduced pressure, and the residue 226 (6), 214 (a), 212 (30), 205 (a), 194 (6), 168 (7), 167 (7), 157 was extracted with dichloromethane (3 X 100 mL). The organic (9), 156 (6), 155 (381,149 (lo), 145 (6), 130 (ll), 129 (61), 122 (7), layers were combined, dried over sodium sulfate, and concentrated. Flash chromatography on silica gel, eluting with 3 2 ether-hexane, 115 (61,114 (56), 111(6), 106 (121,105 (77), 97 (7),92 (7), 91 (59), 89 (17), 75 (14), 73 (24), 72 (55), 71 (ll),70 (lo), 69 (lo), 68 (10). gave 2.16 g of the title compound (70%): TLC R 0.43 (silica gel, 281,211,223,191 nm; (79,5R)-Methyl 3-[(S)-~-Methylbenzyl]-1,2,3,4,5,6,7,8- 3 2 ether-hexane, UV); UV (ethanol) A, octahydro-5-[ (2R)-2-ethyl-2,3-epoxypropyl1-7-( 15-vindoliIR (neat) u,, 3415,3050,2975,2908,2802,1720,1596,1511,1460, 1410,1394,1374,1355,1341,1320,1256,1215,1173,1132,1074, nyl)azonino[6,7-b]indole-7-carboxylate(59). A solution of 0.080 g (0.11 mmol) of (3aR,4R)-methyl 3-[(S)-a-methyl1028,1012,998,968,948,927,860,800,780,734,650,620 cm-'; 250-MHz 'H NMR (CDC13)6 1.47 (d, J = 6.6 Hz,3 H), 2.26-2.44 benzyl]-2,3,3a,4,5,7-hexahydro-4[ (2R)-2-ethyl-2-[ (trimethyl(m,4 H), 2.67-2.87 (m,4 H),4.27 ( q , J = 6.6 Hz, 1 H),7.37-7.50 silyl~oxy]-3-[(p-tolylsulfonyl)oxy]propyl]-l~-pyrrolo[ 2,3-d]car-
'v
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Enantioselective Syntheses of Binary Alkaloids
(m, 3 H), 7.57 (d, J = 7.1 Hz, 1 H), 7.71 (d, J = 8.1 Hz, 1H), 7.81 (d, J 8.6 Hz,1H), 8.41 (d, J = 7.8 Hz,1H); 67.9-MHz '3C NMR (CDCls) 6 18.32,41.59,50.32,60.37,124.06,124.34, 125.32,125.41, 125.61, 127.69, 128.81, 131.67, 134.25, 140.13,209.10;mass spectrum, m/z (re1 intensity) 254 (M 1,271,253 (M+,46), 238 (83), 168 (lo), 156 (le),155 (loo),153 (28), 141 (34), 128 (13), 127 (la), 126 (60), 115 (15), 98 (19); high resolution mass spectrum (EI, mass resolution 5000), M calcd 253.1466547, found 253.14771. N-[(S)-1-( 1-Naphthy1)ethylltetrahydro-y-carboline(49). Phenylhydrazine hydrochloride (1 g, 6.9 mmol) and N-[(S)-l(l-naphthyl)ethyl]-4piperidone(44) (1.6 g, 6.3 "01) were stirred in glacial acetic acid (25 mL) for 3 h at room temperature. Concentrated hydrochloric acid (15 mL) was added and the reaction mixture was heated at 65 OC in an oil bath for 4 h. Acetic acid was removed under reduced pressure and the residue was taken up in dichloromethane (100 mL) and made basic with potassium carbonate. Water was added (50 mL), the organic layer was separated, and the aqueous layer was further extracted with dichloromethane (3 X 50 mL). The combined organic layers were dried over magnesium sulfate and concentrated. Flash chromatography on silica gel, eluting with 41 ether-hexane, gave 1.45 g of the title compound (70%): TLC R, 0.50 (silica gel, 4:l eth282,224,194 nm; IR er-hexane, CAS green); UV (ethanol) ,A, (KBr) Y- 3406,3050,2970,2910,2800,2740,1645,1593,1510, 1472, 1452, 1428,1391,1370,130,1328,1314,1262,1237,1172, 1146,1122,1104,1080,1009,969,800,778,739,634cm-l; 250-MHz 'H NMR (CDC13)6 1.59 (d, J = 6.6 Hz, 3 H),2.38-2.48 (m, 1 H), 2.59-2.68 (m, 2 H), 2.83-2.92 (m, 1 H), 3.64 (d, J = 13.3 Hz, 1 H), 4.10 (d, J = 13.1Hz, 1H), 4.38 (q, J = 6.5 Hz, 1H), 6.99-7.15 (m, 3 H), 7.34-7.50 (m, 4 H), 7.71 (t, J = 7.9 Hz, 2 H),7.80-7.85 (m, 1 H), 8.42-8.45 (m, 1H); 67.9-MHz I3C NMR (CDC13)6 19.52, 24.18,47.29,48.18,61.00, 109.20, 110.58, 117.47, 119.26, 121.06, 124.17,124.17,124.58, 125.32, 125.52,126.45,127.35,128.72,131.75, 132.61,134.20,136.16,141.31; mass spectrum, m/z (re1intensity) 327 (M + 1, ll),326 (M+,35), 311 (4), 171 (30), 155 (32), 144 (23), 143 (loo), 128 (8), 115 (10); high resolution mass spectrum (EI, mass resolution 5000), M calcd 326.1782876, found 326.17844. Dimethyl 3-[ (S)- 1-(1-Naphthy1)ethyll-1,2,3,4,5,6-hexahydroazepino[4,5-b]indole-5,5-dicarboxylate(53). N-[(S)1-(1-Naphthyl)ethyl]tetrahydro-y-carboline (49) (0.49 g, 1.5 mmole) and triethylamine (0.23 mL, 1.65 mmol) in tetrahydrofuran (20 mL) were stirred under nitrogen and brought to -78 OC (dry ice, acetone). tert-Butyl hypochlorite (0.19 mL, 1.65 mmol) was added by syringe, and the mixture was stirred for 15 min and then warmed to 0 OC over 1 h. Thallium dimethyl malonate (0.70 g, 2.10 mmol) was added, the mixture was stirred at room temperature for 14 h and then filtered. The filtrate was then heated at reflux for 24 h. Concentration and flash chromatography on silica gel, eluting with 3 2 ether-hexane, gave 0.56 g (82%)of the title compound: TLC R, 0.69 (silica gel, 4:l ether-hexane, CAS gray); UV (ethanol) ym, 292,281,223,196 nm; IR (film),,v 3440,3048,2955,2900,2835,1740,1510,1488,1460, 1434,1395,1370,1336,1315,1282,1240, 1176,1142,1121,1080, 1050,1024,970,930,800,780,740,700cm-'; 250-MHz 'H NMR (CDC13)6 1.55 (d, J = 6.7 Hz, 3 H), 2.95 (s, 3 H), 2.83-3.03 (m, 3 H), 3.12-3.23 (m, 1 H),3.54 (d, J = 13.2 Hz,1 H), 3.76 (s,3 H), 3.81-3.84 (m, 1 H), 4.72 (q, J = 6.6 Hz, 1 H), 7.04-7.16 (m, 2 H), 7.20-7.26 (m, 1H), 7.39-7.51 (m, 5 H), 7.73-7.83 (m, 2 H), 8.29-8.33 (m, 2 H); 67.9-MHz '3c NMR (CDC13)6 13.22,25.45,52.37,53.07, 54.51,56.82, 61.78, 61.92, 110.78, 115.10, 118.39, 119.29, 122.13, 124.48,124.96,125.02,125.33,125.61,127.77,128.37,128.53,129.53, 132.46,134.09,134.90,138.94,169.05,169.95; mass spectrum, mlz (re1 intensity) 457 (M 1, 18),456 (M', 39), 314 (ll),302 (13), 301 (36), 273 (21), 272 (19), 270 (171, 260 (7), 228 (lo), 227 (131, 214 (7), 159 (35), 156 (17), 155 (loo), 154 (15), 153 (13), 143 (9), 127 (31), 115 (7), 101 (73), 100 (15);high resolution mass spectrum (El, mass resolution 5OOO), M calcd 456.2048916, found 456.20674. Methyl 3 4 (S)-1-( 1-Naphthy1)et hyll- 1,2,3,4,54,6-hexahydroazepino[4,5-b]indole-B-carboxylate(42). A solution of the diester azepine 53 (0.420 g, 0.92 mmol), lithium chloride (0.05 g, 1.18 mmol), and triethylamine hydrochloride (0.63 mg, 0.46 mmol) in dimethylacetamide (20 mL) was heated in an oil bath at 130 O C for 1h. Brine (20 mL) was added and the mixture was extracted with ether (4 X 50 mL). The combined ether layers were dried over magnesium sulfate and concentrated. Flash chromatography on silica gel, eluting with 1:l ether-hexane, gave
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J. Org. Chem., Vol. 56, No. 2, 1991 527 0.25 g (68%) of the title compounds: TLC R, 0.45 (silica, 3:2 291, 281, 223, 191 ether-hexane, CAS blue); UV (ethanol) X, nm; IR (KBr),Y 3375,3050,2974,2940,2900,2825,1734,1597,
1510,1490,1465,1454,1398,1372,1340,1316,1288,1264,1246, 1208,1162,1145,1118,1040,1022,1010,977,910,860,800,780,
740,720,700 cm-'; 270-MHz 'H NMR (CDC13)6 1.51 (d, J = 6.7 Hz, 3 H), 2.79 (8, 3 H), 2.83-3.00 (m, 3 H),3.24-3.30 (m, 1 H), 3.45 (d, J = 5.0 Hz,1 H), 3.54 (dd, J = 12.9, 5.6 Hz, 1 H), 3.73 (dd, J = 5.6, 2.3 Hz, 1 H), 4.71 (4, J = 6.7 Hz, 1 H), 7.04-7.12 (m, 2 H), 7.16-7.19 (m, 1 H), 7.40-7.51 (m, 4 H),7.77-7.85 (m, 2 H), 7.96 (br s, 1 H), 8.41 (d, J = 8.2 Hz,1 H); 67.9-MHz I3C NMR (CDClJ 6 13.58,25.39,46.53,51.45,53.15,56.75,61.14;m&98 spectrum, m/z (re1intensity (398 (M', 34), 244 (14), 243 (65), 215 (18), 214 (43), 202 (7), 183 (5), 169 (12), 156 (23), 155 (loo), 154 (23), 153 (120), 129 (12), 128 (16), 127 (13),115 (12);high resolution mass spectrum (EI, mass resolution 5000), M calcd 398.1994142, found 398.19968. (3aR,4R)- and (3aS,4S)-Methyl 3-[(S)-1-( 1-Naphthyl)ethyl]-2,3,3a,4,5,7-hexahydro-4-[ (2S)-2-ethyl-2,3-dihydroxypropyl]- lH-pyrrOlo[ 2$-d]carbaZole-6-c~boxyrboxylateAcetonide (60 and 61). The mixture of the above azepine diastereomers 42 (0.20 g 0.50 mmol) in toluene (15 mL) was heated at 70 "C. (4S)-4-Ethyl-4,5-dihydroxypentanal acetonide (8a) (0.14 g, 0.75 mmol) in toluene (2 mL) was added slowly by dropping funnel. Upon completion of addition, the mixture was heated at reflux for 36 h. Concentration gave a residue, which was used directly in the following reaction. (3aR,4R)- and (3aS,4S)-Methyl 3-[(S)-1-(1-Naphthyl)-
ethyl]-2,3,3a,4,5,7-hexahydro-4-[ (25)-2-ethy1-2,3-dihydroxypropyl]-1H-pyrrolo[2,3-d]carbazole-6-carboxy1ate(62). The mixture of the above acetonide diastereomers (60,61) and 10% aqueous hydrochloric acid (5 mL) in methanol (20 mL) was heated at reflux for 30 min. Methanol was removed under reduced pressure, and the reaction mixture was made basic with 10% ammonium hydroxide. This solution was then extracted with ether (3 x 50 mL), and the ether layers were combined and dried over magnesium sulfate. Concentration and flash chromatography on silica gel, eluting with ether, gave 0.13 g (50%)of a mixture of the title compounds' diastereomers: TLC R 0.35,0.29 (silica gel, ether, CAS blue); mixture 'H NMR (CDdl,) integration of ethyl triplet 0.55-0.65 (t, 3 H)to 0.75-0.85 (t, 0.75 H). Enantiomeric excess equals 60%. Careful chromatography of the mixture on silica, eluting with ether, gave 0.026 g (10%)of the lesa polar 3aS,4S isomer followed by 0.098 g (37%)of the more polar 3aR,4R isomer 62. For the 3aR,4R isomer 62: UV (ethanol) A, 328, 295, 224, 192 nm; IR (film) u,, 3380,2975,2860,1730,1678,1610,1480, 1468,1440,1380,1282,1250,1205,1114,1045,800,780,743 cm-'; 250-MH~'H NMR (CDC13) 6 0.78 (t,J = 7.5 Hz, 3 H), 0.83492 (m, 2 H), 1.17-1.26 (m, 1 H), 1.43-1.65 (m, 2 H), 1.71 (d, J = 6.7 Hz, 3 H), 1.96-2.10 (m, 2 H), 2.29-2.32 (m, 1 H), 2.56-2.92 (m, 4 H), 3.01 (s, 1 H), 3.25-3.38 (m, 3 H), 3.77 (s, 3 H), 4.71-4.79 (m, 1 H), 6.78-6.80 (m, 2 H), 7.07-7.13 (m, 1 H), 7.46-7.53 (m, 3 H), 7.69 (d, J = 6.8 Hz, 1 H), 7.79 (d, J = 8.1 Hz, 1 H), 7.86 (d, J = 7.6 Hz, 1 H), 8.60 (br s, 1H), 8.85 (br s, 1 H); 67.9-MHz NMR (CDCl3) 6 7.96,22.05,23.14, 28.92,36.03,36.28,41.33,49.90,50.97, 56.01, 67.51, 72.56, 74.61, 90.28, 109.15, 120.61, 122.35, 124.02, 124.98,125.32,125.41,125.70,127.50,127.72,128.81,124.11,137.11, 137.77, 139.98, 142.87, 164.84, 169.02; mass spectrum, m/z (re1 intensity) 527 (M 1, 14), 526 (M', 41) 495 (12), 438 (18),437 (62), 385 (27), 371 (23), 329 (38), 313 (13), 312 (71), 283 (31), 156 (15), 155 (loo), 154 (12), 153 (13), 129 (30). (3aR ,4R ) - M e t h y l 3-1(S) - l - ( 1 - N a p h t h y 1 ) e t h y l l 2,3,3a,4,5,7-hexahydro-4-[( 2 5 )-2-ethyl-2-hydroxy-3-[ (p to~ylsu~fonyl)oxy]propyl]lH-pyrrolo[2,3-d]carbazole-6carboxylate. To a solution of the diol 62 (0.095 g, 0.18 mmol) and triethylamine (50 mL, 0.36 mmol) in dichloromethane (20 mL) at 0 OC was added p-toluenesulfonic anhydride (0.118 g, 0.36 "01) in dichloromethane (2 mL) over a 1-hperiod. The reaction mixture was allowed to warm to room temperature and stirred for 24 h. The solution was then washed with 10% ammonium hydroxide, dried over sodium sulfate, and concentrated to give a white foam, which was used directly in the following reaction: TLC R 0.50 (silica, 4:l ether-hexane, CAS blue). ( 3 a h ,4R ) - M e t h y l 3-[ (S) - l - (1 - N a p h t h y 1 ) e t h y l l 2,3,3a,4,5,7-hexahydro-4-[ (25)-2-ethyl-2-[(trimethylsilyl). 1
'v
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528
J,Org. Chem. 1991,56,528-532
oxy]-3-[ ( p-tolylsulfonyl)oxy]propyl]-lH-pyrrolo[2,3-dIcarbazole6-carboxylate (64). A solution of the hydroxy tusylate from the previous reaction and triethylamine (50 pL, 0.36 m o l ) in tetrahydrofuran (20 mL) was stirred under nitrogen and cooled to 0 "C. Trimethylsilyl trifluoromethanesulfonate (70 kL, 0.36 mmol) was added by syringe and the reaction mixture was stirred for 20 min. Aqueous saturated sodium bicarbonate was added and the THF layer was separated. The aqueous layer was extracted with ether (3 X 50 mL) and the combined organic layers were then dried over sodium sulfate and concentrated. Flash chromatography on silica gel, eluting with 1:l ether-hexane, gave 0.052 g (38%) of the title compound: TLC R, 0.50 (silica, 3:2 ether-hexane, CAS blue); 270-MHz 'H NMR (CDClJ 6 0.00 (9, 9 H), 0.55 (t,J = 7.4 Hz, 3 H), 0.83-0.94 (m, 1 H), 1.05-1.10 (m, 1 H), 1.20 (br s, 1 H), 1.31-1.53 (m, 2 H), 1.60 (d, J = 6.8 Hz, 3 H), 1.90-2.01 (m, 1 H), 2.26-3.30 (m, 1 H), 2.35 (s,3 H), 2.48-2.64 (m, 3 H), 2.79-2.84 (m, 1 H), 3.03 (s, 1 H), 3.73 (8, 3 H), 3.78 (d, J = 9.6 Hz, 1 H), 3.90 (d, J = 9.5 Hz, 1 H), 4.61-4.63 (m, 1 H), 6.70-6.79 (m, 3 H), 7.02-7.08 (m, 1 H), 7.27 (d, J = 8.0 Hz, 2 H), 7.39-7.47 (m, 3 H), 7.60-7.66 (m, 1 HL7.73 ( d , J = 8.3 Hz, 2 HI, 7.78-7.83 (m, 2 H), 8.56 (br s, 1 H), 8.90 (br s, 1 H); mass spectrum, m/z (re1intensity) 752 (M+,2), 611 (2), 538 (9), 437 (25), 384 (9), 302 (4), 283 (14), 279 (13), 268 (3), 229 (12), 205 (5),180 (4), 167 (E),155 (loo), 149 (30), 91 (19). ( 7 5 , 5 R ) - M e t h y l 3-[(5)-1-(1-Naphthyl)ethyl]1,2,3,4,5,6,7,8-octahydro-5[( 2 5 )-2-ethyl-2,3-epoxypropyl]7 4 15-vindolinyl)azonino[5,4-b]indole-7-carboxylate (65). A solution of 0.040 g (0.059 mmol) of (3aR,@)-methyl3-[(S)-l-(lnaphthyl)ethyl]-2,3,3a,4,5,7-hexahydro-4-[ (2S)-2-ethyl-2-[(trimethylsilyl)oxy]-3- [ (p-tolylsulfonyl)oxy]propyl]-1H-pyrrolo[2,3-d]carbazole-6-carboxylate (64) and triethylamine (9.0 pL, 1.1 equiv) in dichloromethane (2 mL) was stirred under nitrogen and brought to 0 "C. tert-Butyl hypochlorite (7.7 pL, 1.1 equiv) in dichloromethane (1 mL) was added by syringe, and the mixture was stirred for 5 min, at which time, TLC showed no remaining starting material. The solution was washed with water (5mL), dried over magnesium sulfate, and concentrated under reduced pressure to give a white foam, which was used directly in the following reaction: TLC R,0.50 (silica gel, 3:2 ether-hexane, CAS purple). To a solution of the chlorination product and vindoline (3,27 mg, 1 equiv) in dry acetone (2 mL) was added tetrafluoroboric acid-diethyl ether complex (19 pL, 2 equiv). The reaction was brought to 0 "C and silver tetrafluoroborate (23 mg, 2 equiv) in acetone (1 mL) was added. The resulting heterogeneous solution was stirred for 10 min, at which time 10% NHIOH (10 mL) was added. The now homogeneous solution was extracted with dichloromethane (3 X 10 mL). The combined organic extracts were dried with magnesium sulfate and concentrated under reduced pressure to give a white foam, which was used directly in the following reaction. The above material was dissolved in glacial acetic acid (5mL) and with stirring potassium borohydride (32 mg, 10 equiv) was
slowly added. After 15 min the solution was poured onto ice and made strongly basic with concentrated ammonium hydroxide. Extraction with dichloromethane (3 X 10 mL), drying (MgSO,), and concentration gave a white foam, which was used directly in the following reaction: TLC R, 0.57 (silica gel, ethyl acetate, CAS brown). To a solution of the above coupled product in tetrahydrofuran (10 mL) at 0 OC was added tetrabutylammonium fluoride (180 pL, 3 equiv, 1 M in THF). The mixture was brought to room temperature and stirred for 15 min, at which time no starting material remained by TLC. The solution was washed with aqueous saturated sodium bicarbonate, dried (MgSO,), and concentrated under vacuum. Flash chromatography on silica gel, eluting with ethyl acetate, gave 0.043 g (72%) of the title compound: TLC R, 0.46 (silica gel, ethyl acetate, CAS brown). 'H NMR shows mostly broad peaks presumably due to interaction of naphthyl group and remainder of compound. Selected peaks for 270-MHz 'H NMR (CDC1,): 6 0.49 (t,J = 7.3 Hz, 3 H, Cl8'), 1.01 (t,J = 7.2 Hz, 3 H, ClS), 2.11 (s, 3 H, OCOCH3), 3.79 (s,6 H, 2 X C0,CH3); mass spectrum, m/z (re1 intensity) 965 (M 1,59), 905 (4), 852 (4), 811 (3), 566 (3), 509 (41,391 (61,253 (4), 242 (7), 239 (3), 214 (5), 201 (3), 197 (3), 195 (5),187 (13), 186 (81), 185 (64), 184 (80), 183 (21), 173 (ll),170 (lo),157 (22), 156 (23), 155 (loo), 154 (17), 153 (lo),143 (9), 142 (57), 113 (4), 100 (4), 99 (61, 97 (4). Vinblastine (1). A solution of the epoxide 65 (0.040 g, 0.041 "01) in methanol (10 mL) was heated at reflux for 40 h, at which time no starting material was present by TLC and a new more polar spot had appeared. The mixture was cooled and 10% palladium on charcoal (5.0 mg) was added. This was then stirred under a hydrogen atmosphere at room temperature for 3 h and filtered, the residue was washed with dichloromethane and methanol, and the filtrates were concentrated under vacuum. The resulting atropisomer 30 was dissolved in dry toluene (10 mL) and heated at reflux for 8 h, at which time TLC showed no remaining starting material and only the presence of vinblastine in its natural conformation.
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Acknowledgment. This work was supported by the Cancer Institute of the National Institutes of Health by grant ROlCA12010. Vindoline was generously supplied by Dr. A. J. Hannart of Omnichem. We are indebted to Dr. L. J. Sears of Montana State University for high resolution mass spectra and to Scott Cowen and Rodney Parsons of our group for low resolution mass spectra Timothy Spitmr provided CD spectra and molecular modeling calculations. Supplementary Material Available: 'H NMR and 'SC N M R spectra for compounds 1,7a, 7b, 13, 14a, 14b, Ma, 19a, 20a, 20b, 21a, 21b, the monotosylates of 20a and 21a, 22a, 22b, 26a, 27a, 30, 31a, 31b, 33a, 33b, 34,35a, and 35b (46 pages). Ordering information is given on current masthead page.
Conversion of D-Glucose to L-Glucose: Oxidative Decarboxylation of a-Oxy Carboxylic Acids via Their Diacyl Peroxides Masao Shiozaki New Lead Research Laboratories, Sankyo Co., Ltd., Hiromachi 1-2-58, Shinagawa-ku, Tokyo 140, Japan
Received May 9,1990 DGlucose was converted to an L-glucose derivative. The key step was the oxidative decarboxylationof carboxylic acid 12 via its diacyl peroxide derivative. This synthetic scheme proceeds through C-glycosidiccompounds and is applicable to other sugar configurations.
Because L sugars are potentially useful as safe, effective, nonnutritive sweeteners,' these less common enantiomers (1) Szarek, W. A.; Hay,G.W.; Vyas, D. M.; Ison, E. R.; Horonowski, L. J. J. Can. J . Chem. 1984,62, 671.
of the carbohydrates have been studied for many years. Chemical syntheses of L-glucose from L-arabinose were reported by Emil Fische9 in 1890 and by J. C. Sowden and (2) Fischer, E. Ber. Dtsch. Chem. Ges. 1890,23, 2611-2624.
0022-3263/91/1956-0528$02.50/00 1991 American Chemical Society
